Method for identifying histone tail proteolysis

ABSTRACT

Although limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, the specific genomic sites targeted for H3NT proteolysis and the functional significance of H3NT cleavage remain largely unknown. Here Applicant reports the first method to identify and examine H3NT-cleaved regions in mammals, called ChIP of acetylated chromatin (ChIPac). By applying ChIPac-Seq to an established cell model of osteoclast differentiation, Applicant discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most H3NT-cleaved genes displayed significant expression changes during osteoclastogenesis. Applicant also discovered that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9). In contrast to other known H3NT proteases, MMP-9 primarily cleaved H3K18-Q19 in vitro and in cells. Furthermore, Applicant&#39;s results support CBP/p300-mediated acetylation of H3K18 as a central regulator of MMP-9 H3NT protease activity both in vitro and at H3NT-cleavage sites during osteoclastogenesis. Importantly, Applicant found that abrogation of H3NT proteolysis impaired osteoclastogenic gene activation concomitant with defective osteoclast differentiation. Applicant&#39;s collective results support the necessity of MMP-9-dependent H3NT proteolysis in regulating gene pathways required for proficient osteoclastogenesis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application No. 62/308,100, filed Mar. 14, 2016, thecontents of which is hereby incorporated by reference into the presentdisclosure.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant No.R01GM084209 awarded by National Institutes of Health (NIH). Thegovernment has certain rights in the invention.

TECHNICAL FIELD

This invention embodies methods and kits related to epigenomics andmedicine. In particular the invention is related to methods ofidentifying cleaved histones and treatment of bone conditions.

BACKGROUND

This disclosure references various publications, patents and publishedpatent specifications by an identifying citation. The full citations forthe disclosures are found immediately preceding the claims. Thedisclosures of these publications, patents and published patentspecifications and all referenced documents are hereby incorporated byreference into the present disclosure in their entirety to more fullydescribe the state of the art to which this invention pertains.

The basic components that comprise the canonical nucleosome coreparticle are evolutionarily conserved in all eukaryotes. Within a livingcell, however, there exists a remarkable degree of heterogeneity innucleosome composition that influences chromatin structure and function(Luger et al. 2012). This is exemplified by the various covalentposttranslational modifications (PTMs) of the N-terminal tails (NT) ofthe core histone proteins (H3, H4, H2A, H2B) that alter nucleosomecomposition to regulate fundamental DNA-templated programs such astranscription (Zentner and Henikoff 2013). For example, acetylation ofthe H3NT can directly facilitate transcription by destabilizingnucleosome structure whereas methylation of the H3NT can indirectlyregulate transcription by binding effector proteins that stimulate orrepress transcription (Bannister et al. 2001; Shogren-Knaak et al.2006). Recent landmark reports determined that differences in the“epigenomic signatures” of several H3NT PTMs are strongly correlated tothe cell type-specific gene expression programs observed in >250 normaland diseased human tissues (Polak et al. 2015; Roadmap Epigenomics etal. 2015). These studies demonstrate that precise alterations of theepigenome are essential in the regulation of gene pathways necessary forthe derivation of normal and aberrant cell types.

Altering epigenomic signatures by “erasing” H3NT PTMs can be achieved byseveral different enzymatic mechanisms. One mechanism is the selectiveremoval of specific H3 PTMs by histone-modifying enzymes such asdeacetylases and demethylases (Black et al. 2012; Seto and Yoshida2014). A more extreme mechanism involves ATP-dependent deposition of anew H3 resulting in the removal of all pre-existing PTMs and associatedinteracting proteins (Narlikar et al. 2013). An alternative intermediatemechanism between the specific and complete erasure of H3 PTMs isproteolysis of the H3NT, which selectively removes pre-existing H3NTPTMs and associated interacting proteins without affecting the H3 coreregion (Azad and Tomar 2014; Dhaenens et al. 2015). While retention ofthe H3 core region preserves nucleosome structure, lack of the H3NTdestabilizes intra- and inter-nucleosomal interactions that may increaseDNA accessibility and facilitate factor binding (Allan et al. 1982;Andresen et al. 2013; Nurse et al. 2013). Therefore, H3NT cleavageprovides an efficient means to rapidly and drastically alter chromatinstructure and function both directly and indirectly.

Although proteolysis of histones within chromatin was first reportedover 55 years ago, the mechanisms and biological functions of histonecleavage remain largely unknown (Phillips and Johns 1959). Proteolysisof the H3NT has been detected in various single and multi-cellulareukaryotes indicating that H3NT cleavage is an evolutionarily conservedprocess that likely functions in epigenetic regulation (Allis et al.1980; Bortvin and Winston 1996; Duncan et al. 2008; Pauli et al. 2010;Duarte et al. 2014; Vossaert et al. 2014). Consistent with this, H3NTcleavage is frequently observed during mammalian developmental programsincluding embryonic stem cell differentiation, mammary gland developmentand myogenesis (Duncan et al. 2008; Asp et al. 2011; Khalkhali-Ellis etal. 2014; Vossaert et al. 2014). The recent identification of CathepsinL and D as the principal H3NT protease during mouse embryonic stem celldifferentiation and mammary gland development, respectively, suggeststhat precursor cells utilize different H3NT proteases in adifferentiation-dependent context (Duncan et al. 2008; Khalkhali-Elliset al. 2014). While these reports imply that targeted H3NT proteolysisat specific genomic regions facilitates differentiation, the lack of amethod to identify H3NT-cleaved regions has precluded significantinsights into the mechanistic functions of H3NT proteolysis. Thus, aneed exists in the art and this disclosure satisfies this need andprovides related advantages as well.

SUMMARY

In this disclosure Applicant demonstrates that matrix metalloproteinase9 (MMP-9) is the principal H3NT protease of osteoclastogenesis.Applicant also developed the first method to map H3NT-cleaved regions inmammals, called “ChIP of acetylated chromatin (ChIPac).” Applicantfurther demonstrates the selective targeting of MMP-dependent H3NTproteolysis near transcription start sites of osteoclastogenic genesduring differentiation. Consistent with H3NT cleavage-dependent geneactivation reported in S. cerevisiae, Applicant discovered that H3NTproteolysis was strongly correlated with transcriptional activation(Santos-Rosa et al. 2009). Abrogation of MMP-9-dependent H3NTproteolysis resulted in impaired osteoclastogenic gene activation anddefective osteoclast differentiation. Therefore, the results reportedherein support a model whereby MMP-9-dependent H3NT proteolysis atosteoclastogenic genes facilitates their activation necessary forproficient osteoclast differentiation.

The DNA in eukaryotic cells is hierarchically packaged by histones toform a highly repressive structure of chromatin. The basic unit ofchromatin is the nucleosome, which consists of 147 bp of DNA wrappedaround an H3-H4 tetramer and a pair of H2A-H2B dimers. Recent reportssuggest that the dynamic modification of chromatin architecture playsfundamental roles in regulating specific gene expression programs.Chromatin architecture can be altered by several different enzymaticmechanisms. One mechanism is the removal of the N-terminal tail domainof histone H3 proteins by specific proteases. This mechanism selectivelyremoves pre-existing H3 tail modifications and associated interactingproteins without affecting the H3 core regions. Thus, it is necessary todetermine the genomic sites targeted for H3 N-terminal tail proteolysisto investigate the role of H3 tail cleavage in transcriptionalregulation. Mapping these cleavage sites could be achieved by ChromatinImmunoprecipitation sequencing (ChIP-seq) analysis, but an antibody thathas specific affinity for the H3 N-terminal tail of all H3 proteins, isnot dependent on or inhibited by existing H3 posttranslationalmodifications and is validated for Chromatin Immunoprecipitation (ChIP)applications, is not available.

To overcome this technical barrier, Applicant developed a novel method,called ChIP of acetylated chromatin (ChIPac), for identification andexamination of genetic loci bound by H3 with N-terminal tail-cleavedregions. The antibody recognizing H3 lysine 14 acetylation (H3K14ac)satisfies the criteria above for ChIP of the H3 N-terminal tailfollowing complete lysine acetylation of crosslinked chromatin in vitroby acetic anhydride. First, cells were fixed with methylene blue tocrosslink chromatin after brief exposure to white light. It should benoted that most ChIP protocols utilize formaldehyde to crosslinkproteins to DNA in vivo. However, because formaldehyde reacts withlysine ε-amino side-chains, which likely precludes complete lysineacetylation by acetic anhydride, methylene blue was used as analternative for cell fixation. Chromatin was isolated and the efficiencyof crosslinking was confirmed by sodium dodecylsulfate-chloroformisoamyl alcohol (SDS-CIA). Fragmented chromatin wasthen treated with acetic anhydride to completely acetylate allunmodified lysine residues in vitro. ChIPac using an H3K14ac-specificantibody selectively enriched H3 N-terminal tail-containing chromatinand simultaneously excluded chromatin lacking the H3 N-terminal tail.ChIPac using an H3 C-terminal tail antibody was performed in parallel asthe normalization control. H3 N-terminal tail-cleaved regions wereidentified by the significant reduction in H3K14ac enrichment relativeto control as determined by quantitative PCR (qPCR) or NextGensequencing analysis.

Thus, in one aspect, provided herein is a method to identify and examineH3 N-terminal tail cleaved regions of a histone, the method comprising,or alternatively consisting essentially of, or yet further consistingof: a) contacting a cell containing chromatin with methylene blue or anequivalent thereof after exposure to white light or an equivalent of thewhite light to crosslink proteins in the cell; b) isolating thechromatin, c) acetylating all unmodified lysine residues by contactingthe chromatin with acetic anhydride; d) conducing ChIPac with an H3C-terminal tail antibody; and e) identifying H3 N-terminal tail-cleavedregions by detecting reduction in H3K14ac enrichment relative to acontrol.

In some aspects of the method, step e. is performed by a methodcomprising, or alternatively consisting essentially of, or yet furtherconsisting of, quantitative PCR (qPCR) or NextGen sequencing analysis.

In another aspect, provided herein is a method to identify apolynucleotide fragment bound to an H3 histone comprising a cleavedN-terminal tail (H3NT) in a cell, the method comprising: a) crosslinkingthe genomic DNA of the cell to the histones of the cell, therebyproducing crosslinked chromatin; b) generating fragments of thecrosslinked chromatin; c) acetylating all unmodified lysine residues inthe histones by contacting the fragmented, crosslinked chromatin withacetic anhydride or an equivalent thereof; d) conducting parallelchromatin immunoprecipitations on the acetylated chromatin produced instep c). with (1) an H3 C-terminal tail control antibody and (2) one ormore antibodies directed to acetylated lysine residues in the cleavedregion of the H3NT; and e) identifying the polynucleotide fragment boundto an H3NT by detecting reduction in polynucleotide fragment enrichmentwith the one or more antibodies directed to acetylated lysine residuesin the cleaved region relative to polynucleotide fragment enrichmentwith the H3 C-terminal tail control antibody.

In other aspects, the method further comprises identifying a subjectappropriate for therapeutic treatment with MMP-9.

In other aspects, the method further comprises identifying genetic lociat which a matrix metalloproteinase or other histone cleavage enzymecleaves an H3 N terminal tail.

Also provided is a kit for identifying a polynucleotide fragment boundto an H3 histone comprising a cleaved N-terminal tail (H3NT) in a cell,the kit comprising: a) acetic anhydride or an equivalent thereof; b) anH3 C-terminal tail control antibody; c) a full length H3 N-taildetection antibody directed to an acetylated lysine residue; and d)instructions for use. In some embodiments, the full length H3 N-taildetection antibody is a H3K14ac antibody. In other embodiments, theantibody is an H3K4ac antibody or an H3K9ac antibody. In someembodiments, a mixture of one or more of H3K14ac antibody, H3K4acantibody, and H3K9ac antibody are used to detect the full lengthacetylated H3 N-terminal tail. In some aspects, the kit may furthercomprise buffers, negative control antibodies, enymes, methylene blue,and/or other reagents necessary to perform chromatinimmunoprecipitation. The standard reagents necessary to performchromatin immunoprecipitation, qPCR, and DNA seq are well known in theart.

Also provided is a method to modulate H3NT proteolysis duringosteoclastogenesis in a cell, comprising, or alternatively consistingessentially of, or yet further consisting of, modulating the activity ofMMP-9 in the cell. In one aspect, H3NT proteolysis is increased byincreasing MMP-9 activity in the cell. In another aspect, the H3NTproteolysis is decreased by depletion or inhibit of MMP-9 activity inthe cell. Diseases or pathological conditions associated with over- orunder-osteoclastogenesis also can be treated by administering to asubject in need thereof an effective amount of the MMP-9 promoting orinhibiting agent. Agents that activate or promote MMP-9 activity includerecombinant or isolated MMP-9 protein and epidermal growth factor hasbeen shown to increase the expression and activity of MMP-9 (see WO2002/045740).

Also provided herein is a method to modulate H3NT proteolysis in a cell,comprising modulating the activity of MMP-9 in the cell. In someaspects, H3NT proteolysis is increased by increasing MMP-9 activity inthe nucleus of the cell. In further aspects, MMP-9 activity is increasedby increasing nuclear localization of MMP-9, increasing acetylation ofH3K18 residues, and/or overexpression of MMP-9. In other aspects, H3NTproteolysis is decreased by depletion or inhibition of MMP-9 activity inthe cell. In further aspects, MMP-9 activity is decreased by knockdownof MMP-9 mRNA, treatment with CBP/p300 inhibitor, and/or treatment witha metalloprotease inhibitor. Knockdown of MMP-9 mRNA can comprisetreatment with MMP-9 shRNA and/or treatment with a mesenchymal stem cellexpressing MMP-9 shRNA.

In the above methods, a cell is a prokaryotic or a eukaryotic cell, andwhen an eukaryotic cell can be a mammalian cell, e.g., a mouse, canine,feline, ovine, simian or a human cell. In the above methods, a cell maybe an osteoclast, an osteoclast precursor cell, or a stem or progenitorcell that can be differentiated into an osteoclast.

Also provided herein is a method to attenuate osteoclast formationand/or differentiation in a subject, comprising, or alternativelyconsisting essentially of, or yet further consisting of, administeringto the subject an effective amount of a MMP-9 agent, inhibitor, oractivator to the subject. In several aspects, the subject is a mammal,e.g., a mouse, a canine, a feline, an ovine, a simian or a humanpatient. These methods can be used therapeutically or in veterinaryapplications, or alternatively, as an animal model to assay for newtherapies or treatments. The agents can be used alone or in combinationwith other known therapies.

Also provided herein is a method of treating a subject with low bonemineral density, comprising administering to the subject an agent thatdecreases or inhibiting the activity of MMP-9 in the subject. In severalaspects, the subject is a mammal, e.g., a mouse, a canine, a feline, anovine, a simian or a human patient. These methods can be usedtherapeutically or in veterinary applications, or alternatively, as ananimal model to assay for new therapies or treatments. The agents can beused alone or in combination with other known therapies. In someaspects, the subject has a bone related disease or condition selectedfrom osteoporosis, bone cancer, cancer that has metastasized to thebone, cancer-induced osteolysis, sepsis, rheumatoid arthritis, andperiodontitis.

Also provided herein is a method of treating a subject with high bonemineral density, comprising administering to the subject an agent thatincreases the activity of MMP-9 in the subject. In several aspects, thesubject is a mammal, e.g., a mouse, a canine, a feline, an ovine, asimian or a human patient. These methods can be used therapeutically orin veterinary applications, or alternatively, as an animal model toassay for new therapies or treatments. The agents can be used alone orin combination with other known therapies. In some aspects, the subjecthas a bone related disease or condition selected from osteopetrosis,pycondysostosis, osteopoikilosis, meloreostosis, sclerosteosis, vanBuchem's disease, LRP5 high bone mass, LRP4 high bone mass,craniometaphyseal dysplaia, Camurati-Engelmann disease, Ghosal syndrome,bone cancer, cancer metastasized to the bone, fluorosis, renalosteodystrophy, acromegaly, hepatitis C-associated osteosclerosis,myelofibrosis, mastocytosis, osseous tuberous sclerosis, Paget'sdisease, and SAPHO syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1G shows identification of MMP-9 as a novel H3NT protease.

FIGS. 1A-1G. FIG. 1A shows primary mouse OCP cells were cultured withRANKL to induce osteoclastogenesis. OCP-induced cells were fixed,stained for TRAP, and photographed under a light microscope (10×) at theindicated days. TRAP-positive cells containing 3 or more nucleirepresent osteoclasts. FIG. 1B shows western blot analysis of chromatinextracted from OCP-induced cells using antibodies recognizing theC-terminal histone regions as indicated. FIG. 1C shows nuclear extractsfrom 3-day OCP-induced cells were fractionated on a P11 column byincreased salt concentration, as indicated, and the in vitro H3NTcleavage assay was performed to identify H3NT active fractions byWestern blot analysis using the H3CT antibody. The indicated H3NT activefractions were fractionated on a Q-Sepharose column followed by a 10-40%glycerol gradient. FIG. 1D shows H3NT cleavage assays of purifiedfractions #3-5 treated with different protease family inhibitors asindicated. FIG. 1E shows H3NT cleavage assays of purified fractions #3-5treated with metalloproteinase inhibitors EDTA, CTT or a selective MMP-9inhibitor. FIG. 1F shows Proteomic analysis of known proteasesidentified in purified fractions #3-5. FIG. 1G shows H3NT cleavageassays using recombinant MMP-9, USP14, USP39 and DIM1.

FIGS. 2A to 2D show MMP-9-dependent H3NT proteolysis duringosteoclastogenesis.

FIGS. 2A-2D. FIG. 2A shows western blot analysis for MMP-9 using wholecell (top) or nuclear (bottom) lysates isolated from OCP-induced cellsat the indicated days. Proform and active MMP-9 are indicated. FIG. 2Bshows gelatin zymography of nuclear lysates isolated from OCP-inducedcells expressing a control (top) or MMP-9-specific (bottom) shRNA at theindicated days. FIG. 2C shows Western blot analysis of nuclear lysatesfrom 3-day OCP-induced cells expressing a control (left) orMMP-9-specific (right) shRNA using the indicated antibodies. FIG. 2Dshows OCP cells transduced with a control or MMP-9-specific shRNA (top)or treated with DMSO control or a selective MMP-9 inhibitor (bottom).H3NT cleavage was assessed at the indicated days post-induction.

FIGS. 3A to 3D show H3K18 is the principal site of MMP-9 proteolysis.

FIGS. 3A-3D. FIG. 3A shows peptide sequences identified by LC-MS/MS ofthe gel-excised rH3 product (H3Δ19) generated by rMMP-9. FIG. 3B showsputative MMP-9 cleavage site identified in the H3NT (aa16-21) in silico.Amino acids that are more (light) or less (dark) conserved in thecanonical MMP-9 consensus sequence are indicated. FIG. 3C shows H3NTcleavage assays using rMMP-9 and rH3 wild type (WT) or mutant substratesas indicated. FIG. 3D shows OCP cells were transduced with WT or mutantH3-FLAG. Chromatin was isolated on the indicated days post-induction forWestern blot analysis using a FLAG antibody to specifically detectproteolysis of H3-FLAG.

FIGS. 4A to 4E show acetylation status of H3K18 regulates MMP-9activity.

FIGS. 4A-4E. FIG. 4A shows the indicated H3 peptides (aa10-35) wereincubated with increasing concentrations of rMMP-9 (x-axis) andproteolysis was measured fluorometrically by reaction of free aminogroups with fluorescamine (y-axis). The V_(max) and K_(m) values wereobtained by non-linear regression fit. FIG. 4B shows H3NT cleavageassays using rMMP-9 and the indicated rH3 acetyl-lysine analoguessubstrates either alone (top) or as reconstituted nucleosome arrays(bottom). FIG. 4C shows H3NT cleavage assays using rMMP-9 andrecombinant (top) or native (bottom) nucleosome array substrates. FIG.4D shows Western blot analysis of nuclear lysates from 3-day OCP-inducedcells expressing a control or CBP/p300-specific shRNA using theindicated antibodies. FIG. 4E shows OCP cells transduced with a controlor CBP/p300-specific shRNA (top) or treated with DMSO control or aselective CBP/p300 inhibitor (bottom). H3NT cleavage was assessed at theindicated days post-induction.

FIGS. 5A to 5D show MMP-9 is required for osteoclastogenic geneactivation and proficient osteoclast differentiation.

FIGS. 5A-5D. FIG. 5A shows scatter plot of RNA-Seq normalized RPKMlevels of annotated genes from 3-day OCP-induced cells expressing acontrol (x-axis) or MMP-9-specific (y-axis) shRNA. Genes withsignificantly increased (light gray) or decreased (dark gray) expressionin MMP-9 depleted cells relative to control cells were defined based onFDR adjusted p<0.05 and log_(e) ratio±0.7. FIG. 5B shows GSEA of the 758genes displaying impaired activation in MMP-9 depleted cells (x-axis)were ranked by increasing expression differences (light curve) relativeto control cells (y-axis). FIG. 5C shows expression differences of theindicated 26 osteoclastogenic genes identified in FIG. 6B betweencontrol (left) and MMP-9 depleted (right) 3-day OCP-induced cellsdisplayed as a heat map in the pseudo color scale indicated. FIG. 5Dshows Visualization (10×) of TRAP stained 5-day OCP-induced cellsexpressing a control, MMP-9-specific or CBP/p300-specific shRNA (top) ortreated with DMSO control, a selective MMP-9 inhibitor or a selectiveCBP/p300 inhibitor (bottom).

FIGS. 6A to 6C show selective targeting of MMP-9-dependent H3NTproteolysis near TSSs during osteoclastogenesis.

FIGS. 6A-6C. FIG. 6A shows schematic of ChIPac-Seq. Cells were fixedwith methylene blue and chromatin extracted. Crosslinked chromatin wassonicated to generate nucleosomes containing full length (left) andNT-cleaved (right) H3. Acetic anhydride was used to artificiallyacetylate all unmodified lysines (indicated as lollipops on the H3).ChIPac was performed for H3CT control, to enrich all nucleosomes, orH3K14ac, to enrich only H3NT-containing nucleosomes. FIG. 6B showsComparative ChIPac-Seq analyses of control (left) and MMP-9 depleted(right) 3-day OCP-induced cells for enrichment (dark) or depletion(light) of H3CT control (left) or H3K14ac (right) near TSS (+/−4 kb) ofall known protein coding genes. K means clustering identified specificH3NT-cleaved TSSs at either promoters (P), coding regions (CR) or both(P+CR). FIG. 6C shows average tag density profiles (y-axis) of eachH3NT-cleaved group near TSS (x-axis) for H3CT and H3K14ac in control andMMP-9 depleted 3-day OCP-induced cells as indicated.

FIGS. 7A to 7D show CBP/p300-mediated acetylation of H3K18 regulates thesites and extent of MMP-9 H3NT proteolysis.

FIGS. 7A-7D. FIG. 7A shows distribution of all H3NT-cleaved genesdisplaying no change (grey) or significantly changed expression (dark)between MMP-9 depleted and control 3-day OCP-induced cells (left).Distribution of H3NT-cleaved genes dependent on MMP-9 for activation(light) or repression (black) in 3-day OCP-induced cells (right). FIG.7B shows fold expression changes (y-axis) of Nfatc1, Lif and Xpr1normalized to β-actin in 3-day OCP-induced cells expressing a control(dark, first two bars in graph), MMP-9-specific (medium gray, middle twobars in each graph) or CBP/p300-specific (light gray, right two bars ineach graph) shRNA relative to non-induced OCP cells. FIG. 7C showsChIPac was performed with H3K14ac-specific (H3NT, left) and H3CT control(right) antibodies in 3-day control (−) or RANKL-induced (+) OCP cellsexpressing a control, MMP-9-specific or CBP/p300-specific shRNA(x-axis). qPCR was performed at the promoters (P, left) and codingregions (CR, right) of Nfatc1 (P-cleaved), Lif (CR-cleaved) and Xpr1(P+C-cleaved). Enrichments were plotted relative to non-induced controlshRNA OCP cells (first column) (y-axis). Star indicates H3NT cleavage.FIG. 7D shows ChIP-qPCR analysis of H3K18ac as described above. Starindicates significantly increased H3K18ac enrichment.

FIGS. 8A-8B. FIG. 8A shows in vitro H3NT cleavage assays performed withthe purified glycerol gradient fractions #3-5 (FIG. 1C) or recombinantMMP-9 (rMMP-9) as indicated. Substrates used in the assays werereconstituted recombinant histone octamer (left), reconstituted octamercontaining purified native histones from HeLa cells (center) orreconstituted native nucleosome arrays (right). Western blot analysiswas performed using antibodies that detect the C-terminal tail of eachindicated core histone (left). FIG. 8B shows in vitro H3NT cleavageassays as described above using recombinant H3.1, H3.2 or H3.3substrates in the absence (left) or presence (right) of rMMP-9.

FIGS. 9A-9B. FIG. 9A shows western blot analysis of cytosolic (left) andnuclear (right) lysates isolated in parallel from OCP-induced cells atthe indicated days for MMP-9, GAPDH (cytosol control) and histone H4(nucleus control). The volumes and total amount of protein (20 μg)loaded per lane were identical in all samples. FIG. 9B shows confocalmicroscopy of OCP-induced cells co-stained for MMP-9 and DAPI at theindicated days (left). OCP cells were grown on glass cover slips, fixedwith 4% paraformaldehyde for 15 min and permeabilized with 0.25% TritonX-100 in phosphate-buffered saline (PBS) for 5 min. Cells were blockedwith PBS+2% goat serum (GS) in PBS for 60 minutes prior to incubationwith an MMP-9 antibody (Santa Cruz). Cells were washed with PBS+GS,incubated with a FITC conjugated secondary antibody (Jackson Laboratory)and mounted with VectaShield with DAPI (Vector Laboratories).

FIGS. 10A-10B. FIG. 10A shows the human histone H3 amino acid sequencewas analyzed by PROSPER (see prosper.erc.monash.edu.au) to identifypredicted sites of H3 proteolysis. The only potential cleavage siteidentified in the H3NT was K18, which was predicted to be cleaved byMMP-9 (inset). FIG. 10B shows the log-odds probabilities of amino acids(y-axis) in the P3-P2′ position (x-axis) of substrates known to beproteolyzed by MMP-9 was generated from PMAP (www.proteolysis.org).

FIGS. 11A-11C. FIG. 11A shows recombinant H3 wild type (WT) and mono-,di- and trimethyl-lysine analogues (top) for H3K4, H3K9, H3K27 and H3K36(left) were used as substrates in in vitro H3NT cleavage assays withrMMP-9. FIG. 11B shows OCP cells were transduced with H3K18acetyltransferase-specific shRNAs as indicated. Knock-down specificityand efficiency of each acetyltransferase shRNA were determined byRT-qPCR to quantitate expression changes relative to control shRNA(y-axis) for each gene (x-axis). FIG. 11C shows chromatin was extractedfrom OCP cells expressing a control or acetyltransferase-specific shRNA(left) at the indicated days post-induction (top) for Western analysiswith the H3CT antibody to detect H3NT proteolysis.

FIGS. 12A-12D. FIG. 12A shows genomic distribution of uniquely mappedRNA-Seq reads from control (dark) and MMP-9 (light) shRNA expressing3-day OCP-induced cells was similar with most reads mapping to codingregions of the mouse genome. FIG. 12B shows gene body coverage plotbetween control (dark) and MMP-9 (light) shRNA expressing 3-dayOCP-induced cells demonstrating a similar uniform coverage across genebodies with no significant 5′ or 3′ bias. FIG. 12C shows gene ontologyanalysis of the 758 genes displaying impaired activation in MMP-9depleted 3-day OCP-induced cells relative to control OCP cells. FIG. 12Dshows OCP cells transduced with a control (grey), MMP-9-specific (dark)or CBP/p300-specific (light) shRNA (left) or cultured with DMSO control(grey), a MMP-9-specific inhibitor (dark) or a CBP/p300 inhibitor(light) (right) were treated with RANKL for 5 days (x-axis). Cells werefixed, stained with a TRAP kit (Sigma) and visualized by lightmicroscopy (10×). The number of osteoclasts (y-axis) was determined bycounting TRAP-positive cells containing 3 or more nuclei in each sample.

FIGS. 13A-13E. FIG. 13A shows OCP cells were crosslinked with differentconcentrations of methylene blue (0, 5, 10 and 20 μM) for the indicatedtimes (x-axis). Chromatin was extracted and DNA-protein crosslinkingefficiency was measured by SDS-chloroform-isoamyl alcohol (SDS-CIA)(y-axis). FIG. 13B shows unmodified and K14ac H3 peptides (aa10-35) andmethylene blue crosslinked chromatin (10 or 20 μM) treated with aceticanhydride were spotted on nitrocellulose for Western analysis with theindicated antibodies. FIG. 13C shows genomic snapshots of the Nfatc1(left), Xpr1 (center) and Lif (right) genes showing the normalizedtracks of H3CT control and H3K14ac ChIPac-Seq data (top) and RNA-Seqdata (bottom) from control and MMP-9 depleted 3-day OCP-induced cells asindicated. Numbers in parentheses indicate maximum sequencing depth foreach sample. Grey boxes indicate the region near TSS (dashed line)displayed in FIG. 6D. FIG. 13D shows heat map showing one dimensionalclustering in a single color channel of all genes displaying H3NTcleavage (FIG. 6B and Table 2). Euclidean distance and average linkagewere used for clustering. Normalized read count values corresponding toeach gene are plotted and colored proportional to the level of readcounts as indicated in the color bar. FIG. 13E shows to investigatepotential functional similarities and differences between the identifiedP, CR and P+CR H3NT-cleaved genes (Table 2), the Wikipathway databasewas queried and a ranked p-value was computed for each pathway from theFisher exact test based on the bionomical distribution and independencefor probability of any gene belonging to any enriched set. The RANKL andseveral osteoclastogenic pathways were significantly enriched (p<0.0001)when all H3NT-cleaved genes were analyzed (dark), consistent withRNA-Seq results (FIG. 12C). These pathways were also significantlyenriched independently for P and CR H3NT-cleaved genes but not for P+CR(brown, p>0.9).

FIG. 14. FIG. 14 shows OCP cells were treated with DMSO control (1), aselective MMP-9 inhibitor (2) or a selective CBP/p300 inhibitor (3) andcultured with (+) or without (−) RANKL for 3 days (x-axis). RT-qPCR wasused to quantitatively measure fold expression changes (y-axis) of theosteoclastogenic genes Nfatc1, Lif and Xpr1 relative to non-inducedcontrol after normalization to β-actin expression.

DETAILED DESCRIPTION Definitions

Before the compositions and methods are described, it is to beunderstood that the invention is not limited to the particularmethodologies, protocols, cell lines, assays, and reagents described, asthese may vary. It is also to be understood that the terminology usedherein is intended to describe particular embodiments of the presentinvention, and is in no way intended to limit the scope of the presentinvention as set forth in the appended claims.

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of tissue culture, immunology,molecular biology, microbiology, cell biology and recombinant DNA, whichare within the skill of the art. See, e.g., Sambrook and Russell eds.(2001) Molecular Cloning: A Laboratory Manual, 3^(rd) edition; theseries Ausubel et al. eds. (2007) Current Protocols in MolecularBiology; the series Methods in Enzymology (Academic Press, Inc., N.Y.);MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press atOxford University Press); MacPherson et al. (1995) PCR 2: A PracticalApproach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual;Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique,5^(th) edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Pat. No.4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization;Anderson (1999) Nucleic Acid Hybridization; Names and Higgins eds.(1984) Transcription and Translation; Immobilized Cells and Enzymes (IRLPress (1986)); Perbal (1984) A Practical Guide to Molecular Cloning;Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells(Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer andExpression in Mammalian Cells; Mayer and Walker eds. (1987)Immunochemical Methods in Cell and Molecular Biology (Academic Press,London); Herzenberg et al. eds (1996) Weir's Handbook of ExperimentalImmunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3^(rd)edition (Cold Spring Harbor Laboratory Press (2002)); Current ProtocolsIn Molecular Biology (F. M. Ausubel, et al. eds., (1987)); the seriesMethods in Enzymology (Academic Press, Inc.): PCR 2: A PracticalApproach (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995));Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual; Harlow andLane, eds. (1999) Using Antibodies, A Laboratory Manual; Animal CellCulture (R. I. Freshney, ed. (1987)); Zigova, Sanberg and Sanchez-Ramos,eds. (2002) Neural Stem Cells.

All numerical designations, e.g., pH, temperature, time, concentration,and molecular weight, including ranges, are approximations which arevaried (+) or (−) by increments of 0.1 or 1 where appropriate. It is tobe understood, although not always explicitly stated that all numericaldesignations are preceded by the term “about”. The term “about” alsoincludes the exact value “X” in addition to minor increments of “X” suchas “X+0.1 or 1” or “X−0.1 or 1,” where appropriate. It also is to beunderstood, although not always explicitly stated, that the reagentsdescribed herein are merely exemplary and that equivalents of such areknown in the art.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise. For example, the term “a cell” includes a plurality of cells,including mixtures thereof.

As used herein, the term “comprising” is intended to mean that thecompositions and methods include the recited elements, but not excludingothers. “Consisting essentially of” when used to define compositions andmethods, shall mean excluding other elements of any essentialsignificance to the combination for the stated purpose. Thus, acomposition consisting essentially of the elements as defined hereinwould not exclude trace contaminants from the isolation and purificationmethod and pharmaceutically acceptable carriers, such as phosphatebuffered saline, preservatives and the like. “Consisting of” shall meanexcluding more than trace elements of other ingredients and substantialmethod steps for administering the compositions of this invention orprocess steps to produce a composition or achieve an intended result.Embodiments defined by each of these transition terms are within thescope of this disclosure.

The term “isolated” as used herein with respect to proteins,polypeptides, cells, nucleic acids, such as DNA or RNA, refers tomolecules separated from other proteins, polypeptides, cells, nucleicacids, such as DNA or RNA, respectively, that are present in the naturalsource of the macromolecule. The term “isolated” as used herein alsorefers to a nucleic acid or peptide that is substantially free ofcellular material, viral material, or culture medium when produced byrecombinant DNA techniques, or chemical precursors or other chemicalswhen chemically synthesized.

As used herein, the term “recombinant” as it pertains to polypeptides orpolynucleotides intends a form of the polypeptide or polynucleotide thatdoes not exist naturally, a non-limiting example of which can be createdby combining polynucleotides or polypeptides that would not normallyoccur together. A recombinant polynucleotide is a polynucleotide createdor replicated using techniques (chemical or using host cells) other thanby a cell in its native environment.

“Cells,” “host cells” or “recombinant host cells” are terms usedinterchangeably herein. It is understood that such terms refer not onlyto the particular subject cell but also to the progeny or potentialprogeny of such a cell. Because certain modifications may occur insucceeding generations due to either mutation or environmentalinfluences, such progeny may not, in fact, be identical to the parentcell, but are still included within the scope of the term as usedherein.

The terms “polynucleotide” and “oligonucleotide” are usedinterchangeably and refer to a polymeric form of nucleotides of anylength, either deoxyribonucleotides or ribonucleotides or analogsthereof. Polynucleotides can have any three-dimensional structure andmay perform any function, known or unknown. The following arenon-limiting examples of polynucleotides: a gene or gene fragment (forexample, a probe, primer, EST or SAGE tag), exons, introns, messengerRNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, dsRNA, siRNA,miRNA, recombinant polynucleotides, branched polynucleotides, plasmids,vectors, isolated DNA of any sequence, isolated RNA of any sequence,nucleic acid probes and primers. A polynucleotide can comprise modifiednucleotides, such as methylated nucleotides and nucleotide analogs. Ifpresent, modifications to the nucleotide structure can be impartedbefore or after assembly of the polynucleotide. The sequence ofnucleotides can be interrupted by non-nucleotide components. Apolynucleotide can be further modified after polymerization, such as byconjugation with a labeling component. The term also refers to bothdouble- and single-stranded molecules. Unless otherwise specified orrequired, any embodiment of this invention that is a polynucleotideencompasses both the double-stranded form and each of two complementarysingle-stranded forms known or predicted to make up the double-strandedform. In some aspects of the disclosed methods, a “polynucleotidefragment” refers to a piece of genomic DNA that has been fragmented by amethod such as sonication or enzymatic fragmentation. Such fragments mayvary in size based on the conditions of the fragmentation. Apolynucleotide fragment may be crosslinked to histones and otherproteins associated with chromatin.

A polynucleotide is composed of a specific sequence of four nucleotidebases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil(U) for thymine when the polynucleotide is RNA. Thus, the term“polynucleotide sequence” is the alphabetical representation of apolynucleotide molecule. This alphabetical representation can be inputinto databases in a computer having a central processing unit and usedfor bioinformatics applications such as functional genomics and homologysearching.

“Amplify” “amplifying” or “amplification” of a polynucleotide sequenceincludes methods such as traditional cloning methodologies, PCR,ligation amplification (or ligase chain reaction, LCR) or otheramplification methods. These methods are known and practiced in the art.See, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202 and Innis et al.(1990) Mol. Cell Biol. 10(11):5977-5982 (for PCR); and Wu et al. (1989)Genomics 4:560-569 (for LCR). In general, the PCR procedure describes amethod of gene amplification which is comprised of (i) sequence-specifichybridization of primers to specific genes within a DNA sample (orlibrary), (ii) subsequent amplification involving multiple rounds ofannealing, elongation, and denaturation using a DNA polymerase, and(iii) screening the PCR products for a band of the correct size. Theprimers used are oligonucleotides of sufficient length and appropriatesequence to provide initiation of polymerization, i.e. each primer isspecifically designed to be complementary to each strand of the genomiclocus to be amplified.

Reagents and hardware for conducting PCR are commercially available.Primers useful to amplify sequences from a particular region arepreferably complementary to, and hybridize specifically to sequences inthe target region or in its flanking regions. Nucleic acid sequencesgenerated by amplification may be sequenced directly. Alternatively theamplified sequence(s) may be cloned prior to sequence analysis. A methodfor the direct cloning and sequence analysis of enzymatically amplifiedgenomic segments is known in the art.

The term “genotype” refers to the specific allelic composition of anentire cell, a certain gene or a specific polynucleotide region of agenome, whereas the term “phenotype’ refers to the detectable outwardmanifestations of a specific genotype.

As used herein, the term “gene” or “recombinant gene” refers to anucleic acid molecule comprising an open reading frame and including atleast one exon and (optionally) an intron sequence. A gene may alsorefer to a polymorphic or a mutant form or allele of a gene.

“Homology” or “identity” or “similarity” refers to sequence similaritybetween two peptides or between two nucleic acid molecules. Homology canbe determined by comparing a position in each sequence that may bealigned for purposes of comparison. When a position in the comparedsequence is occupied by the same base or amino acid, then the moleculesare homologous at that position. A degree of homology between sequencesis a function of the number of matching or homologous positions sharedby the sequences. An “unrelated” or “non-homologous” sequence sharesless than 40% identity, though preferably less than 25% identity, withone of the sequences of the present invention.

A polynucleotide or polynucleotide region (or a polypeptide orpolypeptide region) has a certain percentage (for example, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%) of “sequence identity” toanother sequence means that, when aligned, that percentage of bases (oramino acids) are the same in comparing the two sequences. This alignmentand the percent homology or sequence identity can be determined usingsoftware programs known in the art, for example those described inAusubel et al. eds. (2007) Current Protocols in Molecular Biology.Preferably, default parameters are used for alignment. One alignmentprogram is BLAST, using default parameters. In particular, programs areBLASTN and BLASTP, using the following default parameters: Geneticcode=standard; filter=none; strand=both; cutoff=60; expect=10;Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE;Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDStranslations+SwissProtein+SPupdate+PIR. Details of these programs can befound at the following Internet address: http://www.ncbi.nlm.nih.gov,last accessed on May 21, 2008. Biologically equivalent polynucleotidesare those having the above-noted specified percent homology and encodinga polypeptide having the same or similar biological activity.

In one aspect, the term “equivalent” as it refers to polypeptides,proteins, or polynucleotides refers to polypeptides, proteins, orpolynucleotides, respectively having a sequence having a certain degreeof homology or identity with the reference sequence of the polypeptides,proteins, or polynucleotides (or complement thereof when referring topolynucleotides). A homolog of a double stranded nucleic acid isintended to include nucleic acids having a nucleotide sequence that hasa certain degree of homology with or with the complement thereof. In oneaspect, homologs of nucleic acids are capable of hybridizing to thenucleic acid or complement thereof. In one aspect, an equivalent has atleast 70%, or at least 75% or at least 80%, or at least 85%, or at least90%, or at least 95%, or at least 97%, or at least 98%, sequenceidentity to the reference polynucleotide or polypeptide.

Hybridization reactions can be performed under conditions of different“stringency”. In general, a low stringency hybridization reaction iscarried out at about 40° C. in about 10×SSC or a solution of equivalentionic strength/temperature. A moderate stringency hybridization istypically performed at about 50° C. in about 6×SSC, and a highstringency hybridization reaction is generally performed at about 60° C.in about 1×SSC. Hybridization reactions can also be performed under“physiological conditions” which is well known to one of skill in theart. A non-limiting example of a physiological condition is thetemperature, ionic strength, pH and concentration of Mg²⁺ normally foundin a cell.

As used herein, the term “oligonucleotide” refers to polynucleotidessuch as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleicacid (RNA). The term should also be understood to include, asequivalents, derivatives, variants and analogs of either RNA or DNA madefrom nucleotide analogs, and, as applicable to the embodiment beingdescribed, single (sense or antisense) and double-strandedpolynucleotides. Deoxyribonucleotides include deoxyadenosine,deoxycytidine, deoxyguanosine, and deoxythymidine. For purposes ofclarity, when referring herein to a nucleotide of a nucleic acid, whichcan be DNA or an RNA, the terms “adenosine”, “cytidine”, “guanosine”,and “thymidine” are used. It is understood that if the nucleic acid isRNA, a nucleotide having a uracil base is uridine.

A “gene delivery vehicle” is defined as any molecule that can carryinserted polynucleotides into a host cell. Examples of gene deliveryvehicles are liposomes, biocompatible polymers, including naturalpolymers and synthetic polymers; lipoproteins; polypeptides;polysaccharides; lipopolysaccharides; artificial viral envelopes; metalparticles; and bacteria, or viruses, such as baculovirus, adenovirus andretrovirus, bacteriophage, cosmid, plasmid, fungal vectors and otherrecombination vehicles typically used in the art which have beendescribed for expression in a variety of eukaryotic and prokaryotichosts, and may be used for gene therapy as well as for simple proteinexpression.

“Gene delivery,” “gene transfer,” and the like as used herein, are termsreferring to the introduction of an exogenous polynucleotide (sometimesreferred to as a “transgene”) into a host cell, irrespective of themethod used for the introduction. Such methods include a variety ofwell-known techniques such as vector-mediated gene transfer (by, e.g.,viral infection, sometimes called transduction), transfection,transformation or various other protein-based or lipid-based genedelivery complexes) as well as techniques facilitating the delivery of“naked” polynucleotides (such as electroporation, “gene gun” deliveryand various other techniques used for the introduction ofpolynucleotides). Unless otherwise specified, the term transfected,transduced or transformed may be used interchangeably herein to indicatethe presence of exogenous polynucleotides or the expressed polypeptidetherefrom in a cell. The introduced polynucleotide may be stably ortransiently maintained in the host cell. Stable maintenance typicallyrequires that the introduced polynucleotide either contains an origin ofreplication compatible with the host cell or integrates into a repliconof the host cell such as an extrachromosomal replicon (e.g., a plasmid)or a nuclear or mitochondrial chromosome. A number of vectors are knownto be capable of mediating transfer of genes to mammalian cells, as isknown in the art and described herein.

The term “express” refers to the production of a gene product.

As used herein, “expression” refers to the process by whichpolynucleotides are transcribed into RNA such as mRNA and/or the processby which a transcribed mRNA is subsequently translated into peptides,polypeptides, or proteins. If the polynucleotide is derived from genomicDNA, expression may include splicing of the mRNA in an eukaryotic cell.

A “gene product” or alternatively a “gene expression product” refers tothe amino acid (e.g., peptide or polypeptide) generated when a gene istranscribed and translated.

“Under transcriptional control” is a term well understood in the art andindicates that transcription of a polynucleotide sequence, usually a DNAsequence, depends on its being operatively linked to an element whichcontributes to the initiation of, or promotes, transcription.“Operatively linked” intends the polynucleotides are arranged in amanner that allows them to function in a cell.

The term “encode” as it is applied to polynucleotides refers to apolynucleotide which is said to “encode” a polypeptide if, in its nativestate or when manipulated by methods well known to those skilled in theart, it can be transcribed and/or translated to produce the mRNA for thepolypeptide and/or a fragment thereof. The antisense strand is thecomplement of such a nucleic acid, and the encoding sequence can bededuced therefrom.

A cell that “stably expresses” an exogenous polypeptide is one thatcontinues to express a polypeptide encoded by an exogenous geneintroduced into the cell either after replication if the cell isdividing or for longer than a day, up to about a week, up to about twoweeks, up to three weeks, up to four weeks, for several weeks, up to amonth, up to two months, up to three months, for several months, up to ayear or more.

As used herein, a “vector” is a vehicle for transferring geneticmaterial into a cell. Examples of such include, but are not limited toplasmids and viral vectors. A viral vector is a virus that has beenmodified to transduct genetic material into a cell. A plasmid vector ismade by splicing a DNA construct into a plasmid. As is apparent to thoseof skill in the art, the appropriate regulatory elements are included inthe vectors to guide replication and/or expression of the geneticmaterial in the selected host cell.

A “viral vector” is defined as a recombinantly produced virus or viralparticle that comprises a polynucleotide to be delivered into a hostcell, either in vivo, ex vivo or in vitro. Examples of viral vectorsinclude retroviral vectors, lentiviral vectors, adenovirus vectors,adeno-associated virus vectors, alphavirus vectors and the like.Alphavirus vectors, such as Semliki Forest virus-based vectors andSindbis virus-based vectors, have also been developed for use in genetherapy and immunotherapy. See, Schlesinger and Dubensky (1999) Curr.Opin. Biotechnol. 5:434-439 and Ying et al. (1999) Nat. Med.5(7):823-827.

In aspects where gene transfer is mediated by a retroviral vector, avector construct refers to the polynucleotide comprising the retroviralgenome or part thereof, and a therapeutic gene. As used herein,“retroviral mediated gene transfer” or “retroviral transduction” carriesthe same meaning and refers to the process by which a gene or nucleicacid sequences are stably transferred into the host cell by virtue ofthe virus entering the cell and integrating its genome into the hostcell genome. The virus can enter the host cell via its normal mechanismof infection or be modified such that it binds to a different host cellsurface receptor or ligand to enter the cell. Retroviruses carry theirgenetic information in the form of RNA; however, once the virus infectsa cell, the RNA is reverse-transcribed into the DNA form whichintegrates into the genomic DNA of the infected cell. The integrated DNAform is called a provirus. As used herein, retroviral vector refers to aviral particle capable of introducing exogenous nucleic acid into a cellthrough a viral or viral-like entry mechanism. A “lentiviral vector” isa type of retroviral vector well-known in the art that has certainadvantages in transducing nondividing cells as compared to otherretroviral vectors. See, Trono D. (2002) Lentiviral Vectors, New York:Spring-Verlag Berlin Heidelberg.

In aspects where gene transfer is mediated by a DNA viral vector, suchas an adenovirus (Ad) or adeno-associated virus (AAV), a vectorconstruct refers to the polynucleotide comprising the viral genome orpart thereof, and a transgene. Adenoviruses (Ads) are a relatively wellcharacterized, homogenous group of viruses, including over 50 serotypes.See, e.g., International PCT Application No. WO 95/27071. Ads do notrequire integration into the host cell genome. Recombinant Ad derivedvectors, particularly those that reduce the potential for recombinationand generation of wild-type virus, have also been constructed. See,International PCT Application Nos. WO 95/00655 and WO 95/11984.Wild-type AAV has high infectivity and specificity integrating into thehost cell's genome. See, Hermonat and Muzyczka (1984) Proc. Natl. Acad.Sci. USA 81:6466-6470 and Lebkowski et al. (1988) Mol. Cell. Biol.8:3988-3996.

Vectors that contain both a promoter and a cloning site into which apolynucleotide can be operatively linked are well known in the art. Suchvectors are capable of transcribing RNA in vitro or in vivo, and arecommercially available from sources such as Stratagene (La Jolla,Calif.) and Promega Biotech (Madison, Wis.). In order to optimizeexpression and/or in vitro transcription, it may be necessary to remove,add or alter 5′ and/or 3′ untranslated portions of the clones toeliminate extra, potential inappropriate alternative translationinitiation codons or other sequences that may interfere with or reduceexpression, either at the level of transcription or translation.Alternatively, consensus ribosome binding sites can be insertedimmediately 5′ of the start codon to enhance expression.

Gene delivery vehicles also include several non-viral vectors, includingDNA/liposome complexes, and targeted viral protein-DNA complexes.Liposomes that also comprise a targeting antibody or fragment thereofcan be used in the methods of this invention. To enhance delivery to acell, the nucleic acid or proteins of this invention can be conjugatedto antibodies or binding fragments thereof which bind cell surfaceantigens, e.g., a cell surface marker found on stem cells.

A “plasmid” is an extra-chromosomal DNA molecule separate from thechromosomal DNA which is capable of replicating independently of thechromosomal DNA. In many cases, it is circular and double-stranded.Plasmids provide a mechanism for horizontal gene transfer within apopulation of microbes and typically provide a selective advantage undera given environmental state. Plasmids may carry genes that provideresistance to naturally occurring antibiotics in a competitiveenvironmental niche, or alternatively the proteins produced may act astoxins under similar circumstances.

“Plasmids” used in genetic engineering are called “plasmic vectors”.Many plasmids are commercially available for such uses. The gene to bereplicated is inserted into copies of a plasmid containing genes thatmake cells resistant to particular antibiotics and a multiple cloningsite (MCS, or polylinker), which is a short region containing severalcommonly used restriction sites allowing the easy insertion of DNAfragments at this location. Another major use of plasmids is to makelarge amounts of proteins. In this case, researchers grow bacteriacontaining a plasmid harboring the gene of interest. Just as thebacteria produces proteins to confer its antibiotic resistance, it canalso be induced to produce large amounts of proteins from the insertedgene. This is a cheap and easy way of mass-producing a gene or theprotein it then codes for.

“Eukaryotic cells” comprise all of the life kingdoms except monera. Theycan be easily distinguished through a membrane-bound nucleus. Animals,plants, fungi, and protists are eukaryotes or organisms whose cells areorganized into complex structures by internal membranes and acytoskeleton. The most characteristic membrane-bound structure is thenucleus. A eukaryotic host, including, for example, yeast, higher plant,insect and mammalian cells. Non-limiting examples include simian,bovine, ovine, porcine, murine, rats, canine, equine, feline, avian,reptilian and human.

“Prokaryotic cells” that usually lack a nucleus or any othermembrane-bound organelles and are divided into two domains, bacteria andarchaea. Additionally, instead of having chromosomal DNA, these cells'genetic information is in a circular loop called a plasmid. Bacterialcells are very small, roughly the size of an animal mitochondrion (about1-2 μm in diameter and 10 μm long). Prokaryotic cells feature threemajor shapes: rod shaped, spherical, and spiral. Instead of goingthrough elaborate replication processes like eukaryotes, bacterial cellsdivide by binary fission. Examples include but are not limited toprokaryotic Cyanobacteria, bacillus bacteria, E. coli bacterium, andSalmonella bacterium.

The term “propagate” means to grow a cell or population of cells. Theterm “growing” also refers to the proliferation of cells in the presenceof supporting media, nutrients, growth factors, support cells, or anychemical or biological compound necessary for obtaining the desirednumber of cells or cell type.

The term “culturing” refers to the in vitro propagation of cells ororganisms on or in media of various kinds. It is understood that thedescendants of a cell grown in culture may not be completely identical(i.e., morphologically, genetically, or phenotypically) to the parentcell.

A “probe” when used in the context of polynucleotide manipulation refersto an oligonucleotide that is provided as a reagent to detect a targetpotentially present in a sample of interest by hybridizing with thetarget. Usually, a probe will comprise a label or a means by which alabel can be attached, either before or subsequent to the hybridizationreaction. Suitable labels are described and exemplified herein.

A “primer” is a short polynucleotide, generally with a free 3′-OH groupthat binds to a target or “template” potentially present in a sample ofinterest by hybridizing with the target, and thereafter promotingpolymerization of a polynucleotide complementary to the target. A“polymerase chain reaction” (“PCR”) is a reaction in which replicatecopies are made of a target polynucleotide using a “pair of primers” ora “set of primers” consisting of an “upstream” and a “downstream”primer, and a catalyst of polymerization, such as a DNA polymerase, andtypically a thermally-stable polymerase enzyme. Methods for PCR are wellknown in the art, and taught, for example in MacPherson et al. (1991)PCR: A Practical Approach, IRL Press at Oxford University Press. Allprocesses of producing replicate copies of a polynucleotide, such as PCRor gene cloning, are collectively referred to herein as “replication.” Aprimer can also be used as a probe in hybridization reactions, such asSouthern or Northern blot analyses. Sambrook et al., supra. The primersmay optionall contain detectable labels and are exemplified anddescribed herein.

As used herein, the term “detectable label” intends a directly orindirectly detectable compound or composition (other than a naturallyoccurring polynucleotide in its natural environment) that is conjugateddirectly or indirectly to the composition to be detected, e.g.,polynucleotide or protein such as an antibody so as to generate anartificial, non-naturally occurring “labeled” composition. The term alsoincludes sequences conjugated to the polynucleotide that will provide asignal upon expression of the inserted sequences, such as greenfluorescent protein (GFP) and the like. The label may be detectable byitself (e.g. radioisotope labels or fluorescent labels) or, in the caseof an enzymatic label, may catalyze chemical alteration of a substratecompound or composition which is detectable. The labels can be suitablefor small scale detection or more suitable for high-throughputscreening. As such, suitable labels include, but are not limited toradioisotopes, fluorochromes, chemiluminescent compounds, dyes, andproteins, including enzymes. The label may be simply detected or it maybe quantified. A response that is simply detected generally comprises aresponse whose existence merely is confirmed, whereas a response that isquantified generally comprises a response having a quantifiable (e.g.,numerically reportable) value such as an intensity, polarization, and/orother property. In luminescence or fluorescence assays, the detectableresponse may be generated directly using a luminophore or fluorophoreassociated with an assay component actually involved in binding, orindirectly using a luminophore or fluorophore associated with another(e.g., reporter or indicator) component.

Examples of luminescent labels that produce signals include, but are notlimited to bioluminescence and chemiluminescence. Detectableluminescence response generally comprises a change in, or an occurrenceof, a luminescence signal. Suitable methods and luminophores forluminescently labeling assay components are known in the art anddescribed for example in Haugland, Richard P. (1996) Handbook ofFluorescent Probes and Research Chemicals (6^(th) ed.). Examples ofluminescent probes include, but are not limited to, aequorin andluciferases.

Examples of suitable fluorescent labels include, but are not limited to,fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosin,coumarin, methyl-coumarins, pyrene, Malacite green, stilbene, LuciferYellow, Cascade Blue™, and Texas Red. Other suitable optical dyes aredescribed in the Haugland, Richard P. (1996) Handbook of FluorescentProbes and Research Chemicals (6^(th) ed.).

In another aspect, the fluorescent label is functionalized to facilitatecovalent attachment to a cellular component present in or on the surfaceof the cell or tissue such as a cell surface marker. Suitable functionalgroups, including, but not are limited to, isothiocyanate groups, aminogroups, haloacetyl groups, maleimides, succinimidyl esters, and sulfonylhalides, all of which may be used to attach the fluorescent label to asecond molecule. The choice of the functional group of the fluorescentlabel will depend on the site of attachment to either a linker, theagent, the marker, or the second labeling agent.

Attachment of the fluorescent label may be either directly to thecellular component or compound or alternatively, can by via a linker.Suitable binding pairs for use in indirectly linking the fluorescentlabel to the intermediate include, but are not limited to,antigens/antibodies, e.g., rhodamine/anti-rhodamine, biotin/avidin andbiotin/strepavidin.

The phrase “solid support” refers to non-aqueous surfaces such as“culture plates” “gene chips” or “microarrays.” Such gene chips ormicroarrays can be used for diagnostic and therapeutic purposes by anumber of techniques known to one of skill in the art. In one technique,oligonucleotides are attached and arrayed on a gene chip for determiningthe DNA sequence by the hybridization approach, such as that outlined inU.S. Pat. Nos. 6,025,136 and 6,018,041. The polynucleotides of thisinvention can be modified to probes, which in turn can be used fordetection of a genetic sequence. Such techniques have been described,for example, in U.S. Pat. Nos. 5,968,740 and 5,858,659. A probe also canbe attached or affixed to an electrode surface for the electrochemicaldetection of nucleic acid sequences such as described by Kayem et al.U.S. Pat. No. 5,952,172 and by Kelley et al. (1999) Nucleic Acids Res.27:4830-4837.

Various “gene chips” or “microarrays” and similar technologies are knownin the art. Examples of such include, but are not limited to, LabCard(ACLARA Bio Sciences Inc.); GeneChip (Affymetric, Inc); LabChip (CaliperTechnologies Corp); a low-density array with electrochemical sensing(Clinical Micro Sensors); LabCD System (Gamera Bioscience Corp.); OmniGrid (Gene Machines); Q Array (Genetix Ltd.); a high-throughput,automated mass spectrometry systems with liquid-phase expressiontechnology (Gene Trace Systems, Inc.); a thermal jet spotting system(Hewlett Packard Company); Hyseq HyChip (Hyseq, Inc.); BeadArray(Illumina, Inc.); GEM (Incyte Microarray Systems); a high-throughputmicroarry system that can dispense from 12 to 64 spots onto multipleglass slides (Intelligent Bio-Instruments); Molecular BiologyWorkstation and NanoChip (Nanogen, Inc.); a microfluidic glass chip(Orchid Biosciences, Inc.); BioChip Arrayer with four PiezoTippiezoelectric drop-on-demand tips (Packard Instruments, Inc.); FlexJet(Rosetta Inpharmatic, Inc.); MALDI-TOF mass spectrometer (Sequnome);ChipMaker 2 and ChipMaker 3 (TeleChem International, Inc.); andGenoSensor (Vysis, Inc.) as identified and described in Heller (2002)Annu. Rev. Biomed. Eng. 4:129-153. Examples of “gene chips” or a“microarrays” are also described in U.S. Patent Publication Nos.:2007/0111322; 2007/0099198; 2007/0084997; 2007/0059769 and 2007/0059765and U.S. Pat. Nos. 7,138,506; 7,070,740 and 6,989,267.

In one aspect, “gene chips” or “microarrays” containing probes orprimers homologous to a polynucleotide described herein are prepared. Asuitable sample is obtained from the patient, extraction of genomic DNA,RNA, protein or any combination thereof is conducted and amplified ifnecessary. The sample is contacted to the gene chip or microarray panelunder conditions suitable for hybridization of the gene(s) or geneproduct(s) of interest to the probe(s) or primer(s) contained on thegene chip or microarray. The probes or primers may be detectably labeledthereby identifying the sequence(s) of interest. Alternatively, achemical or biological reaction may be used to identify the probes orprimers which hybridized with the DNA or RNA of the gene(s) of interest.The genotypes or phenotype of the patient is then determined with theaid of the aforementioned apparatus and methods.

It is to be inferred without explicit recitation and unless otherwiseintended, that when the present technology relates to a polypeptide,protein, polynucleotide or antibody, an equivalent or a biologicallyequivalent of such is intended within the scope of the presenttechnology.

As used herein, the “administration” of an agent or drug to a subject orsubject includes any route of introducing or delivering to a subject acompound to perform its intended function. Suitable dosage formulationsand methods of administering the agents are known in the art. Route ofadministration can also be determined and method of determining the mosteffective route of administration are known to those of skill in the artand will vary with the composition used for treatment, the purpose ofthe treatment, the health condition or disease stage of the subjectbeing treated and target cell or tissue. Non-limiting examples of routeof administration include oral administration, vaginal, nasaladministration, injection, topical application and by suppository.Administration includes self-administration and the administration byanother. It is also to be appreciated that the various modes oftreatment or prevention of medical conditions as described are intendedto mean “substantial”, which includes total but also less than totaltreatment or prevention, and wherein some biologically or medicallyrelevant result is achieved.

Administration can be effected in one dose, continuously orintermittently throughout the course of treatment. Methods ofdetermining the most effective means and dosage of administration areknown to those of skill in the art and will vary with the compositionused for therapy, the purpose of the therapy, the target cell beingtreated and the subject being treated. Single or multipleadministrations can be carried out with the dose level and pattern beingselected by the treating physician.

As used herein, the term “animal” is used synonymously with “patient” or“subject” and refers to living multi-cellular vertebrate organisms, acategory that includes, for example, mammals and birds. The term“mammal” includes both human and non-human mammals. Similarly, the term“subject” or “patient” includes both human and veterinary subjects, forexample, humans, non-human primates, dogs, cats, sheep, mice, horses,and cows.

The term “crosslinking” refers to a method of chemically joining two ormore molecules by a covalent bond. Crosslinking methods allow for thestabilization of molecular structures and the capture of molecularinteractions within a cell so that they can be preserved and studied.Crosslinking may also involve “fixation” of a cell or tissue by whichsaid cell or tissue is preserved from decay and degradation, thuspreventing cell lysis or putrefaction. Non-limiting examples offixatives include heat fixation and chemical fixation. Chemicalfixatives include crosslinking fixatives such as aldehydes which causecovalent chemical bonds between proteins and molecules in a cell,precipitating fixatives such as alcohols that reduce the solubility ofprotein molecules and acetic acid, oxidizing agents that react withprotein side chains and other biological molecules to allow formation ofcrosslinks, mercurial, picrates that react with histones and basicproteins to form crystalline picrates with amino acids, andhepes-glutamic acid buffer-mediated organic solvent protection effect.Crosslinking reagents appropriate for use with the disclosed methodsinclude but are not limited to formaldehyde, paraformaldehyde, methyleneblue with or without exposure to white light, sodium fluorescein,acridine orange, cisplatin, dimethylarsinic acid, potassium chromate,ultraviolet light, and lasers.

The term “acetylation” generally refers to the chemical reaction whichattaches one or more acetyl functional groups (chemical formula CH₃CO,sometimes referred to as the symbol “Ac”) to a chemical compound.Acetylation may also refer to the status of a particular chemical moietywith respect to its degree of modification with acetyl groups.“Deacetylation” is the removal of an acetyl group from a chemicalcompound. An acetylation reaction involves the replacement of thehydrogen atom of a hydroxyl group with an acetyl group to yield anacetate ester. Lysine amino acid residues are common targets for proteinacetylation. For example, histones are acetylated and deacetylated onlysine residues of their N-terminal tails. Such histone acetylation anddeacetylation reactions can be catalyzed by a class of enzymes withhistone acetyltransferase (HAT) activity or histone deacetylase (HDAC)activity, respectively. HAT enzymes include but are not limited to theGNAT superfamily including Gcn5, SAGA, SLIK, STAGA, ADA, A2, Gcn5L,p300/CREB-binding protein associated factor (PCAF), Elp3, HPA2, andHAT1), the MYST family including MOZ (Monocytic Leukemia Zinc FingerProtein), Ybf2/Sas3, Sas2, Tip60, Esa1, MOF, MORF, and HBO1, thep300/CBP family including adenoviral E1A associated protein of 300 kDa(p300) and to CREB-binding protein (CBP), and other HATs such as steroidreceptor coactivator 1 (SRO), ATF-2, and TAFI1250. Acetyl-Coenzyme A isa common source of the acetyl group transferred to a target histonelysine residue by HAT enzymes.

Acetic anhydride (also known as ethanoic anhydride, chemical formulaCH₃CO₂O) is a common acetylating agent. Acetic anhydride acetylationreactions can occur in the presence of an acid or base catalyst. Metalsalts and triflates such as CoCl₂, TiCl4-AgCLO₄, TaCL₅, TaCl₅—SiO₂,Ce(III) triflate, Sn(IV) porphyrine, Sc(OTf)₃, MeSiOTf, In(OTf)₃,Cu(OTf)₂, Bi(OTf)₃, bis(cyclopentadienyl) zirconium dichloride, I₂, and1,3,-dibromo-5,5-dimethylhydentoin, trichloroisocyanuric acid can beused in combination with acid anhydride. Equivalents of acetic anhydrideinclude but are not limited to HAT enzymes, priopionic anhydride,deuterated acetic anhydride, acetic acid, acetyl chloride, acetyl-CoA,and formic anhydride. An equivalent of acetic anhydride has the propertyof being the donating source of an acetyl group to modify a histonelysine residue and/or catalyzing a histone lysine acetylation reaction.

The term “chromatin” refers to the complex of biological molecules foundin the nucleus of a cell, comprising, e.g., DNA, protein (includinghistones), and RNA. Histones are alkaline proteins found in nuclei thatcan function to package the nucleic acid. The fundamental unit ofchromatin is the nucleosome which comprises about 146 base pairs of DNAwrapped about 1.7 times in a left-handed turn around a protein octamerof two each of the core histones H3, H4, H2A and H2B. Alternatively, theoctamer may be comprised of one or more variant histones includingH3.3,centromeric H3 variant (cenH3, called also CENPA), H3.1, H3.2, TSH3.4, H3.5, H3.Y, H2A.X, H2A.Z, H2A.Z.2, H2A.B, H2A.L, H2A.P, H2A.1,H2B.1, H2A.J, H2B.1, H2B.W, H2B.Z, H2B.E. H1 and H5 linker histones aregenerally located between nucleosomes. Histones can controlaccessibility and expression of the region of DNA (or specific locus)around which they are bound or regions of DNA with which they associate.For example, histones with repressive modifications to their N-terminaltails tend to promote tightly compacted chromatin that preventstranscriptional machinery from accessing the DNA. In contrast, histoneswith modifications to their N-terminal tails that increase access to theDNA tend to promote chromatin with high levels of gene expression. Inaddition to histones and nucleic acids, chromatin may also compriseproteins that associate with DNA such as transcription machinery(including RNA polymerases), DNA replication machinery, andtranscription factors or repressors.

The term “chromatin immunoprecipitation” (ChIP) refers to a method usedto study the interaction between nucleic acids and proteins in thechromatin of a cell. This method can be combined with DNA detectiontechniques to determine whether specific proteins or proteinmodifications are associated with specific genomic regions, or loci. Ingeneral, the DNA, RNA, and proteins of chromatin are first crosslinkedtogether to preserve their interactions. Next, the crosslinked chromatinis sheared to break the DNA crosslinked to proteins into fragments. Thenan antibody directed to a protein of interest is incubated with thefragmented chromatin. The antibody may be directly bound to a magneticbead or a secondary antibody bound to a magnetic bead may be added.Alternatively, a non-magnetic purification strategy such as an affinitytag may be used. Next, the antibody-bound chromatin fragments areimmunoprecipitated by purification with a magnetic column or analternate purification method. Finally, the protein is unlinked from theprecipitated chromatin and the DNA is purified. Standard detectiontechniques can be used to identify the precipitated DNA such as PCR,quantitative PCR, and DNA sequencing. Further details for ChIPtechniques and optimization can be found in Chapter 20 of Sambrook andRussell eds. (2012) Molecular Cloning: A Laboratory Manual, 4th edition,incorporated by reference herein. In some aspects, the disclosed methodsutilize specialized ChIP techniques to capture three dimensionalchromatin structures as they occur in living cells. These specializedChIP methods include but are not limited to Chromatin ConformationCapture (3C), Circularized Chromosome Conformation Capture (4C), CarbonCopy Chromosome Conformation Capture (5C), ChIP-Loop, Hi-C, andCapture-C. These methods are reviewed in de Wit et al. Genes andDevelopment 2012 (26: 11-24), incorporated by reference herein.

The term “antibody” refers to a polyclonal, monoclonal, recombinant, orsynthetic immunoglobulin molecule that specifically binds a targetantigen. In one aspect, monoclonal antibodies are excluded. In anotherembodiment, polyclonal antibodies or other naturally occurringantibodies are excluded. The term includes intact immunoglobulinmolecules, fragments or polymers of those immunoglobulin molecules,chimeric antibodies containing sequences from more than one species,class, or subclass of immunoglobulin, and human or humanized versions ofimmunoglobulin molecules or fragments thereof containing a least theidiotype of an immunoglobulin that specifically binds the targetantigen. Target antigens relevant for the disclosed methods include butare not limited to the C-terminus of histone H3, H3 acetylated lysineresidue 4, H3 acetylated lysine residue 9, and H3 acetylated lysineresidue 14. Antibodies directed to the cleaved N-terminal tail andappropriate for use with the disclosed methods include but are notlimited to Acetyl-Histone H3 (Lys9) Antibody (17H12L11), ABfinity RabbitMonoclonal (ThermoFisher), Acetyl-Histone H3 (Lys9) Antibody (17HCLC),ABfinity Rabbit Oligoclonal (ThermoFisher), Acetyl-Histone H3 (Lys9)Antibody (2HCLC), Abfinity Rabbit Oligoclonal (ThermoFisher),Acetyl-Histone H3 (Lys14) Polyclonal Antibody (ThermoFisher),Acetyl-Histone H3 (Lys18) Polyclonal Antibody (ThermoFisher),Acetyl-Histone H3 (Lys9) Monoclonal Antibody (J.924.2) (ThermoFisher),Acetyl-Histone H3 (Lys9, Lys14) Polyclonal Antibody (ThermoFisher),Acetyl-Histone H3 (Lys4) Polyclonal Antibody (ThermoFisher),Acetyl-Histone H3 (Lys9) Polyclonal Antibody (ThermoFisher),Acetyl-Histone H3 (Lys9) Monoclonal Antibody (ThermoFisher),Acetyl-Histone H3 (Lys9, Lys14) Polyclonal Antibody (ThermoFisher),Anti-Histone H3 (acetyl K9) antibody-ChIP Grade (ab10812) (Abcam),Anti-Histone H3 (acetyl K9) antibody-ChIP Grade (ab4441) (abcam),Anti-Histone H3 (acetyl K18) antibody-ChIP Grade (ab1191) (abcam),Anti-Histone H3 (acetyl K14) antibody [EP964Y]-ChIP Grade (ab52946), andAnti-Histone H3 (acetyl K9) antibody [AH3-120]-ChIP Grade (ab12179)(abcam), or an equivalent of each thereof. An equivalent antibody is anantibody that has similar target reactivity (i.e. directed to anacetylated lysine residue in the N-terminal tail of histone H3), and canbe used for chromatin immunoprecipitation. Equivalents also includeantibodies with the same or similar target reactivity or idiotype thatare conjugated to labels such as fluorochromes or epitope tags such asbiotin.

The term “idiotype” refers to the portion of an immunoglobulin moleculethat confers the molecule's ability to bind an antigen. The idiotype ofan antibody is determined by the complementarity determining regions(CDRs) of the immunoglobulin variable domains (V_(L) and V_(H)).

Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IVcollagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, aclass of enzymes that belong to the zinc-metalloproteinases familyinvolved in the degradation of the extracellular matrix. The sequence ofthe human protein is found under GenBank reference number NP_004985 andthe mRNA encoding the protein is found under NM_004994. The murinecounterpart is found under NP_038627 and the mRNA is found underNM_013599. In some aspects, the protein sequence of MMP-9 is (SEQ ID NO:22), disclosed below.

Additional matrix metallopeptidases that are relevant for the disclosedmethods include: Matrix metalloproteinases with potential histone tailcleavage activity include but are not limited to MMP1 (interstitialcollagenase, human mRNA: NM_002421, NM_001145938; protein: NP_001139410,NP_002412), MMP2 (Gelatinase-A, 72 kDa gelatinase, human mRNA:NM_004530, NM_001127891, NM_001302508, NM_001302509, NM_001302510;protein: NP_001121363, NP_001289437, NP_001289438, NP_001289439,NP_004521), MMP3 (Stromelysin 1, human mRNA: NM_002422; protein:NP_002413), MMP7, (Matrilysin, Pump1, human mRNA: NM_002423; protein:NP_002414), MMP8 (Neutrophil collagenase, human mRNA: NM_001304441,NM_001304442, NM_002424; protein: NP_001291370, NP_001291371,NP_002415), MMP10 (Stromelysin 2, human mRNA: NM_002425; protein:NP_002416), MMP11 (Stromelysin 3, human mRNA: NM_005940; protein:NP_005931, NP_005931.2), MMP12 (Macrophage metalloelastase, human mRNA:NM_002426; protein: NP_002417), MMP13 (Collagenase3, human mRNA:NM_002427; protein: NP_002418), MMP14 (MT1-MMP, human mRNA: NM_004995;protein: NP_004986), MMP15 (MT2-MMP, human mRNA: NM_002428; protein:NP_002419), MMP16 (MT3-MMP, human mRNA: NM_005941, NM_022564, NM_032297;protein: NP_005932), MMP17 (MT4-MMP, human mRNA: NM_016155; protein:NP_057239, NP_057239.4), MMP18 (Collagenase 4, xcol4, xenopuscollagenase), MMP19 (RASI-1, Stromelysin 4, human mRNA: NM_001032360,NM_001272101, NM_002429, NM_022790, NM_022792; protein: NP_001259030,NP_002420), MMP20 (Enamelysin, human mRNA: NM_004771; protein:NP_004762), MMP21 (XMMP, human mRNA: NM_147191; protein: NP_671724),MMP23A (CA-MMP), MMP23B (human mRNA: NM_006983, protein: NP_008914),MMP24 (MT5-MMP, human mRNA: NM_006690; protein: NP_006681), MMP25(MT6-MMP, human mRNA: NM_004142, NM_022468, NM_022718; protein:NP_071913), MMP26 (Matrilysin-2, endometase, human mRNA: NM_021801;protein: NP_068573), MMP27 (MMP-22, C-MMP, human mRNA: NM_022122;protein: NP_071405), MMP28 (Epilysin, human mRNA: NM_001032278,NM_024302, NM_032950, protein: NP_001027449, NP_077278, NP_116568,NP_116568.1).

The term “inhibitor” refers to a molecule (often a small molecule) thatacts to block a function of a desired target protein. An equivalent ofan MMP-9 inhibitor is one that blocks MMP-9 function and/or its importto the nucleus.

The term “peptide” or “polypeptide” can be used to refer to a natural orsynthetic molecule comprising two or more amino acids linked by thecarboxyl group of one amino acid to the alpha amino group of another.The peptide is not limited by length; thus “peptide” can includepolypeptides and proteins.

The term “peptidomimetic” refers to a mimetic of a peptide whichincludes some alteration of the normal peptide chemistry.Peptidomimetics typically enhance some property of the original peptide,such as increase stability, increased efficacy, enhanced delivery,increased half life, etc.

The term “aptamer” refers to an oligonucleic acid molecule thatspecifically binds to a target molecule.

As used herein, the term “small molecule” refers to a compound having amolecular weight of less than 1000 Daltons, and typically between 300and 700 Daltons. The term may include monomers or primary metabolites,secondary metabolites, a biological amine, a steroid, or synthetic ornatural, non-peptide biological molecule(s). In the context of targetedimaging probes that are small molecules, the small molecule canspecifically bind the molecular or cellular target.

The term “specifically recognizes” or “specifically binds” refers to therecognition or binding of a molecule to a target molecule, such as anantibody to its cognate antigen, while not significantly binding toother molecules. Preferably, a molecule “specifically binds” to a targetmolecule with an affinity constant (Ka) greater than about 10⁵ mol⁻¹(e.g., 10⁶ mol⁻¹, 10⁷ mol⁻¹, 10⁸ mol⁻¹, 10⁹ mol⁻¹, 10¹⁰ mol⁻¹, 10¹¹mol⁻¹, and 10¹² mol⁻¹ or more) with the target molecule.

The term “subject” or “patient” refers to any individual who is thetarget of administration. The subject can be a vertebrate, for example,a mammal. Thus, the subject can be a human. The subject can bedomesticated, agricultural, or zoo- or circus-maintained animals.Domesticated animals include, for example, mice, dogs, cats, rabbits,ferrets, guinea pigs, hamsters, pigs, monkeys or other primates, andgerbils. Agricultural animals include, for example, horses, mules,donkeys, burros, cattle, cows, pigs, sheep, and alligators. Zoo- orcircus-maintained animals include, for example, lions, tigers, bears,camels, giraffes, hippopotamuses, and rhinoceroses. The term does notdenote a particular age or sex.

By “treatment” and “treating” is meant the medical management of asubject with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. It is understood that treatment, while intendedto cure, ameliorate, stabilize, or prevent a disease, pathologicalcondition, or disorder, need not actually result in the cure,ameliorization, stabilization or prevention. The effects of treatmentcan be measured or assessed as described herein and as known in the artas is suitable for the disease, pathological condition, or disorderinvolved. Such measurements and assessments can be made in qualitativeand/or quantitative terms. Thus, for example, characteristics orfeatures of a disease, pathological condition, or disorder and/orsymptoms of a disease, pathological condition, or disorder can bereduced to any effect or to any amount.

In some aspects, the diseases or conditions that can be treated by thedisclosed methods include but are not limited to low bone mineraldensity (BMP), high BMP, osteoporosis, bone cancer, cancer that hasmetastasized to the bone, cancer-induced osteolysis, sepsis, rheumatoidarthritis, periodontitis, osteopetrosis, pycondysostosis,osteopoikilosis, meloreostosis, sclerosteosis, van Buchem's disease,LRP5 high bone mass, LRP4 high bone mass, craniometaphyseal dysplasia,Camurati-Engelmann disease, Ghosal syndrome, bone cancer, cancermetastasized to the bone, fluorosis, renal osteodystrophy, acromegaly,hepatitis C-associated osteosclerosis, myelofibrosis, mastocytosis,osseous tuberous sclerosis, Paget's disease, and SAPHO syndrome. Thedisclosed methods can also be used to treat or identify a cell or tissuein need of histone N-terminal tail cleavage. In some aspects, thedisclosed methods can be used to treat or identify a subject in ofincreased, decreased, or inhibited osteoclastogenesis.

It is to be inferred without explicit recitation and unless otherwiseintended, that when the present invention relates to a polypeptide,protein, polynucleotide or antibody, an equivalent or a biologicallyequivalent of such is intended within the scope of this invention. Asused herein, the term “biological equivalent thereof” is intended to besynonymous with “equivalent thereof” when referring to a referenceprotein, antibody, fragment, polypeptide or nucleic acid, intends thosehaving minimal homology while still maintaining desired structure orfunctionality. Unless specifically recited herein, it is contemplatedthat any polynucleotide, polypeptide or protein mentioned herein alsoincludes equivalents thereof. In one aspect, an equivalentpolynucleotide is one that hybridizes under stringent conditions to thepolynucleotide or complement of the polynucleotide as described hereinfor use in the described methods. In another aspect, an equivalentantibody or antigen binding polypeptide intends one that binds with atleast 70%, or alternatively at least 75%, or alternatively at least 80%,or alternatively at least 85%, or alternatively at least 90%, oralternatively at least 95% affinity or higher affinity to a referenceantibody or antigen binding fragment. In another aspect, the equivalentthereof competes with the binding of the antibody or antigen bindingfragment to its antigen under a competitive ELISA assay. In anotheraspect, an equivalent intends at least about 80% homology or identityand alternatively, at least about 85%, or alternatively at least about90%, or alternatively at least about 95%, or alternatively 98% percenthomology or identity and exhibits substantially equivalent biologicalactivity to the reference protein, polypeptide or nucleic acid. In oneaspect, a biological equivalent of an antibody means one having theability of the antibody to selectively bind its epitope protein orfragment thereof as measured by ELISA or other suitable methods.Biologically equivalent antibodies include, but are not limited to,those antibodies, peptides, antibody fragments, antibody variant,antibody derivative and antibody mimetics that bind to the same epitopeas the reference antibody.

A polynucleotide or polynucleotide region (or a polypeptide orpolypeptide region) having a certain percentage (for example, 80%, 85%,90%, or 95%) of “sequence identity” to another sequence means that, whenaligned, that percentage of bases (or amino acids) are the same incomparing the two sequences. The alignment and the percent homology orsequence identity can be determined using software programs known in theart, for example those described in Current Protocols in MolecularBiology (Ausubel et al., eds. 1987) Supplement 30, section 7.7.18, Table7.7.1. Preferably, default parameters are used for alignment. Apreferred alignment program is BLAST, using default parameters. Inparticular, preferred programs are BLASTN and BLASTP, using thefollowing default parameters: Genetic code=standard; filter=none;strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50sequences; sort by=HIGH SCORE; Databases=non-redundant,GenBank+EMBL+DDBJ+PDB+GenBank CDStranslations+SwissProtein+SPupdate+PIR. Details of these programs can befound at the following Internet address: ncbi.nlm.nih.gov. Sequenceidentity and percent identity were determined by incorporating them intoclustalW.

A “composition” as used herein, intends an active agent, such as acompound as disclosed herein and a carrier, inert or active. The carriercan be, without limitation, solid such as a biotin, a bead or a resin,or liquid, such as phosphate buffered saline.

An “effective amount” is an amount sufficient to effect beneficial ordesired results. An effective amount can be administered in one or moreadministrations, applications or dosages. Such delivery is dependent ona number of variables including the time period for which the individualdosage unit is to be used, the bioavailability of the therapeutic agent,the route of administration, etc. It is understood, however, thatspecific dose levels of the therapeutic agents disclosed herein for anyparticular subject depends upon a variety of factors including theactivity of the specific compound employed, bioavailability of thecompound, the route of administration, the age of the animal and itsbody weight, general health, sex, the diet of the animal, the time ofadministration, the rate of excretion, the drug combination, and theseverity of the particular disorder being treated and form ofadministration. In general, one will desire to administer an amount ofthe compound that is effective to achieve a serum level commensuratewith the concentrations found to be effective in vivo. Theseconsiderations, as well as effective formulations and administrationprocedures are well known in the art and are described in standardtextbooks. Consistent with this definition and as used herein, the term“therapeutically effective amount” is an amount sufficient to treat aspecified disorder or disease or alternatively to obtain apharmacological response.

Modes for Carrying Out the Disclosure

This disclosure provides a method to identify to identify apolynucleotide fragment and or genomic locus bound to an H3 histonecomprising a cleaved N-terminal tail (H3NT) in a cell, the methodcomprising, or alternatively consisting essentially of, or yet furtherconsisting of the following steps: first crosslinking chromatin proteinsincluding histones to the genomic DNA present in the cell by contactingthe cell or a cell extract such as nuclear extract with an effectiveamount of methylene blue or an equivalent of methylene blue, subsequentto the cell having been exposed to white light or an equivalent of thewhite light. Methylene blue (chemical formula C₁₆H₁₈CIN₃S) is also knownas methylthionium is a medication and a dye. Methylene blue iscommercially available from number of vendors, for example Tocris,Spectrum, and MD Supplies. Non-limiting examples of an equivalent tomethylene blue include sodium fluorescein, acridine orange, cisplatin,dimethylarsinic acid, potassium chromate, ultraviolet light, and lasers.Most ChIP protocols utilize formaldehyde to crosslink proteins to DNA invivo. However, because formaldehyde reacts with lysine ε-aminoside-chains, which likely precludes complete lysine acetylation byacetic anhydride, methylene blue is used as an alternative for cellfixation. As used herein any cell containing chromatin can be used inthe assay, e.g., a plant cell or a eukaryotic cell, and cells that arein culture. Non-limiting examples of eukaryotic cells include animalcell, mammalian cells (e.g. any species, canine, feline, equine) orhuman cells. In one aspect the cell is a human cell. In some aspects,the cell is an osteoclast, osteoclast precursor, or a progenitor cell orstem cell capable of differentiation into an osteoclast. Cells capableof differentiation into an osteoclast include but are not limited toembryonic stem cells, induced pluripotent cells, hematopoietic stemcells, myeloid stem cells, granulocyte-macrophage colony forming unit(GM-CFU), monocyte precursor (CFU-M), progenitor cells, andpre-osteoclasts.

After the chromatin in the cell is cross-linked, it is isolated from thecell and the efficiency of crosslinking is confirmed by any appropriatemethod, e.g., by sodium dodecyl sulfate-chloroformisoamyl alcohol(SDS-CIA). Unmodified lysine residues are acetylated by treatment orcontacting with an effective amount of acetic anhydride or otheracetylation agent. The fragmented chromatin is then contacted inparallel with either (1) an effective amount of an H3 C-terminal controlantibody or (2) an effective amount of a H3K14ac-specific antibody.Alternatively, the chromatin may be contacted with another antibodyspecific for a lysine residue N-terminal (upstream) of the cleavage siteof interest such as an H3K4ac or H3K9ac antibody. In another aspect, amixture of two or more of H3K14ac, H3K4ac, and H3K9ac antibodies is usedto enrich for uncleaved H3. The two parallel antibody-bound fragmentedchromatin samples are then selectively enriched by immunoprecipitation.The antibody is a monoclonal or a polyclonal antibody. In one aspect,use of the H3 C-terminal tail antibody is performed in parallel with thenormalization control. H3 N-terminal tail-cleaved regions are identifiedby the significant reduction in H3K14ac enrichment relative to control,e.g., as determined by quantitative PCR (qPCR) or NextGen DNA sequencinganalysis.

Also provided herein is a method for identification and examination ofgenetic loci bound by H3 with N-terminal tail-cleaved regions. First,cells are fixed with methylene blue or an equivalent thereof tocrosslink chromatin after brief exposure to white light. It should benoted that most ChIP protocols utilize formaldehyde to crosslinkproteins to DNA in vivo. However, because formaldehyde reacts withlysine ε-amino side-chains, which likely precludes complete lysineacetylation by acetic anhydride, methylene blue was used as analternative for cell fixation. Chromatin was isolated and the efficiencyof crosslinking was confirmed by sodium dodecylsulfate-chloroformisoamyl alcohol (SDS-CIA). Fragmented chromatin wasthen treated with acetic anhydride to completely acetylate allunmodified lysine residues in vitro. ChIPac using an H3K14ac-specificantibody selectively enriched H3 N-terminal tail-containing chromatinand simultaneously excluded chromatin lacking the H3 N-terminal tail.ChIPac using an H3 C-terminal tail antibody was performed in parallel asthe normalization control. H3 N-terminal tail-cleaved regions wereidentified by the significant reduction in H3K14ac enrichment relativeto control as determined by quantitative PCR (qPCR) or NextGensequencing analysis.

This method can also be used to identify and monitor other histone tailproteolysis processes. For example, the cysteine protease capthepsin Lhas been reported to cleave H3 in murine embryonic stem cells at severalcleavage sites, including between alanine residue 21 and threonineresidue 22 and between lysine residue 27 and serine residue 28. Becausethese cleavage sites are downstream (i.e. closer to the C-terminus ofH3) of the recognition site for the detection antibodies used herein(i.e. H3K14, H3K9, and/or H3K4), the methods disclosed herein can beused to detect the location of capthepsinL cleaved histone H3 in thegenome of a cell. As long as the detection antibody is directed to anacetylated residue upstream (i.e. closer to the N-terminus) of theputative H3 tail cleavage site, a cleaved histone genome bindinglocation can be identified through the disclosed methods. Thus, thedisclosed methods can be used detect the genomic loci of histone H3cleaved at the following sites: alanine residue 21, arginine residue 26,or alanine residue 31 as reported in embryonic stem cells; betweenlysine 23 and alanine 24 or between lysine 27 and serine 28 as reportedin chickens and catalyzed by the glutamate dehydrogenase enzyme; betweenalanine 21 and threonine 22 as reported in saccharomyces cerevisiae andcatalyzed by the purified vacuolar protease B enzyme; and betweenleucine 20 and alanine 21. In other aspects, this method can be used toidentify and monitor lysis of other histone tails such as histone H2A,H2B, and H4 using antibodies specific to the cleaved portion of the H2A,H2B, or H4 in conjunction with antibodies to the C-terminal portion ofthese histones.

Thus, in one aspect, provided herein is a method to identify and examineH3 N-terminal tail cleaved regions of a histone, the method comprising,or alternatively consisting essentially of, or yet further consistingof: a) contacting a cell containing chromatin with methylene blue or anequivalent thereof after exposure to white light or an equivalent of thewhite light to crosslink proteins in the cell; b) isolating thechromatin, c) acetylating all unmodified lysine residues by contactingthe chromatin with acetic anhydride; d) conducing ChIPac with an H3C-terminal tail antibody; and e) identifying H3 N-terminal tail-cleavedregions by detecting reduction in H3K14ac enrichment relative to acontrol.

In some aspects of the method, step e. is performed by a methodcomprising, or alternatively consisting essentially of, or yet furtherconsisting of, quantitative PCR (qPCR) or NextGen sequencing analysis.

In another aspect, provided herein is a method to identify apolynucleotide fragment bound to an H3 histone comprising a cleavedN-terminal tail (H3NT) in a cell, the method comprising: a) crosslinkingthe genomic DNA of the cell to the histones of the cell, therebyproducing crosslinked chromatin; b) generating fragments of thecrosslinked chromatin; c) acetylating all unmodified lysine residues inthe histones by contacting the fragmented, crosslinked chromatin withacetic anhydride or an equivalent thereof; d) conducting parallelchromatin immunoprecipitations on the acetylated chromatin produced instep c). with (1) an H3 C-terminal tail control antibody and (2) one ormore antibodies directed to acetylated lysine residues in the cleavedregion of the H3NT; and e) identifying the polynucleotide fragment boundto an H3NT by detecting reduction in polynucleotide fragment enrichmentwith the one or more antibodies directed to acetylated lysine residuesin the cleaved region relative to polynucleotide fragment enrichmentwith the H3 C-terminal tail control antibody.

In some aspects of the method, step a) is performed by fixation withmethylene blue or an equivalent thereof.

In some aspects of the method, step b) is performed by sonication,enzymatic fragmentation, or an equivalent of each thereof.

In some aspects of the method, the one or more antibodies directed toacetylated lysine residues in the cleaved region of the H3NT in stepd)(2) are selected from an H3K4ac antibody, an H3K9ac antibody, and anH3K14ac antibody.

In some aspects of the method, the one or more antibodies directed toacetylated lysine residues in the cleaved region of the H3NT in stepd)(2) is an H3K14ac antibody.

In some aspects of the method, step e) is performed by a methodcomprising quantitative PCR (qPCR) or NextGen sequencing analysis.

In other aspects, the method further comprises identifying a subjectappropriate for therapeutic treatment with MMP-9.

In other aspects, the method further comprises identifying genetic lociat which a matrix metalloproteinase or other histone cleavage enzymecleaves an H3 N terminal tail. Matrix metalloproteinases with potentialhistone tail cleavage activity include MMP1 (interstitial collagenase),MMP2 (Gelatinase-A, 72 kDa gelatinase), MMP3 (Stromelysin 1), MMP1,(Matrilysin, Pump1), MMP8 (Neutrophil collagenase), MMP9 (Gelatinase-B,92 kDa gelatinase), MMP10 (Stromelysin 2), MMP11 (Stromelysin 3), MMP12(Macrophage metalloelastase), MMP13 (Collagenase3), MMP14 (MT1-MMP),MMP15 (MT2-MMP), MMP16 (MT3-MMP), MMP17 (MT4-MMP), MMP18 (Collagenase 4,xcol4, xenopus collagenase), MMP19 (RASI-1, Stromelysin 4), MMP20(Enamelysin), MMP21 (XMMP), MMP23A (CA-MMP), MMP23B, MMP24 (MT5-MMP),MMP25 (MT6-MMP), MMP26 (Matrilysin-2, endometase), MMP2? (MMP-22,C-MMP), MMP28 (Epilysin).

Also provided is a kit for identifying a polynucleotide fragment boundto an H3 histone comprising a cleaved N-terminal tail (H3NT) in a cell,the kit comprising: a) acetic anhydride or an equivalent thereof; b) anH3 C-terminal tail control antibody; c) a full length H3 N-taildetection antibody directed to an acetylated lysine residue; and d)instructions for use. In some embodiments, the full length H3 N-taildetection antibody is a H3K14ac antibody. In other embodiments, theantibody is an H3K4ac antibody or an H3K9ac antibody. In someembodiments, a mixture of one or more of H3K14ac antibody, H3K4acantibody, and H3K9ac antibody are used to detect the full lengthacetylated H3 N-terminal tail. In some aspects, the kit may furthercomprise buffers, negative control antibodies, enymes, methylene blue,and/or other reagents necessary to perform chromatinimmunoprecipitation. The standard reagents necessary to performchromatin immunoprecipitation, qPCR, and DNA seq are well known in theart.

Also provided is a method to modulate H3NT proteolysis duringosteoclastogenesis in a cell, comprising, or alternatively consistingessentially of, or yet further consisting of, modulating the activity ofMMP-9 in the cell. In one aspect, H3NT proteolysis is increased byincreasing MMP-9 activity in the cell. In another aspect, the H3NTproteolysis is decreased by depletion or inhibit of MMP-9 activity inthe cell. Diseases or pathological conditions associated with over- orunder-osteoclastogenesis also can be treated by administering to asubject in need thereof an effective amount of the MMP-9 promoting orinhibiting agent. Agents that activate or promote MMP-9 activity includerecombinant or isolated MMP-9 protein and epidermal growth factor hasbeen shown to increase the expression and activity of MMP-9 (see WO2002/045740). In some aspects, the agent is selected from recombinantMMP-9, recombinant MMP-9 modified to include nuclear localizationsignals, a histone acetyltransferase enzyme with H3K18 specificity, andgene therapy with a polynucleotide encoding MMP-9. Agents that inhibitor decrease MMP-9 activity are known in the art, e.g., as described inUS Patent Appl. No. 2017/0015647; 2013/0064878; and 2011/00114186, andincorporated herein by reference. In some aspects, the agent is selectedfrom MMP-9 shRNA, a mesenchymal stem cell expressing MMP-9 shRNA, aCBP/p300 inhibitor, an MMP-9 inhibitor, or a metalloprotease inhibitor.In some aspects, inhibitors appropriate for use with the disclosedmethods include but are not limited to inhibitors of MMP-9 such as2-(N-Benzyl-4-methoxyphenylsulfonamido)-5-((diethylamino)methyl)-N-hydroxy-3-methylbenzamide,actinonin, marimastat, MMP Inhibitor V, Batimastat, Chlorhexidine,dihydrochloride, GM 6001, MMP Inhibitor II, cis-ACCP, SB-3CT,4-Aminobenzoyl-Gly-Pro-D-Leu-D-Ala hydroxamic acid, keracyanin chloride,MMP2/MMP-9 Inhibitor I, MMP-2/MMP-9 Inhibitor II, MMP-9 Inhibitor I,MMP-9/MMP-13 inhibitor I, MMP-9/MMP-13 inhibitor II, MMP-2/MMP-9Inhibitor V, CP 471474, Ageladine A, TFA, or an equivalent of eachthereof. The above-listed MMP inhibitors are available from Abcam orSanta Cruz Biotech.

Also provided herein is a method to modulate H3NT proteolysis in a cell,comprising modulating the activity of MMP-9 in the cell. In someaspects, H3NT proteolysis is increased by increasing MMP-9 activity inthe nucleus of the cell. In further aspects, MMP-9 activity is increasedby increasing nuclear localization of MMP-9, increasing acetylation ofH3K18 residues, and/or overexpression of MMP-9. In other aspects, H3NTproteolysis is decreased by depletion or inhibition of MMP-9 activity inthe cell. In further aspects, MMP-9 activity is decreased by knockdownof MMP-9 mRNA, treatment with CBP/p300 inhibitor, and/or treatment witha metalloprotease inhibitor. Knockdown of MMP-9 mRNA can comprisetreatment with MMP-9 shRNA and/or contacting the cell with an effectiveamount of a mesenchymal stem cell expressing MMP-9 shRNA.

In the above methods, a cell is a prokaryotic or a eukaryotic cell, andwhen an eukaryotic cell can be a mammalian cell, e.g., a mouse, canine,feline, ovine, simian or a human cell. In the above methods, a cell maybe an osteoclast, an osteoclast precursor cell, or a stem or progenitorcell that can be differentiated into an osteoclast.

Also provided herein is a method to attenuate osteoclast formationand/or differentiation in a subject, comprising, or alternativelyconsisting essentially of, or yet further consisting of, administeringto the subject an effective amount of a MMP-9 agent, inhibitor, oractivator to the subject. In several aspects, the subject is a mammal,e.g., a mouse, a canine, a feline, an ovine, a simian or a humanpatient. These methods can be used therapeutically or in veterinaryapplications, or alternatively, as an animal model to assay for newtherapies or treatments. The agents can be used alone or in combinationwith other known therapies.

Also provided herein is a method of treating a subject with low bonemineral density, administering an agent or inhibitor that decreases orinhibits the activity of MMP-9 in the subject. In several aspects, thesubject is a mammal, e.g., a mouse, a canine, a feline, an ovine, asimian or a human patient. These methods can be used therapeutically orin veterinary applications, or alternatively, as an animal model toassay for new therapies or treatments. The agents can be used alone orin combination with other known therapies. In some aspects, the subjecthas a bone related disease or condition selected from osteoporosis, bonecancer, cancer that has metastasized to the bone, cancer-inducedosteolysis, sepsis, rheumatoid arthritis, and periodontitis. Agents thatinhibit or decrease MMP-9 activity are known in the art, e.g., asdescribed in US Patent Appl. No. 2017/0015647; 2013/0064878; and2011/00114186, and incorporated herein by reference. In some aspects,the agent is selected from MMP-9 shRNA, a mesenchymal stem cellexpressing MMP-9 shRNA, a CBP/p300 inhibitor, an MMP-9 inhibitor, or ametalloprotease inhibitor. In some aspects, inhibitors appropriate foruse with the disclosed methods include but are not limited to inhibitorsof MMP-9 such as2-(N-Benzyl-4-methoxyphenylsulfonamido)-5-((diethylamino)methyl)-N-hydroxy-3-methylbenzamide,actinonin, marimastat, MMP Inhibitor V, Batimastat, Chlorhexidine,dihydrochloride, GM 6001, MMP Inhibitor II, cis-ACCP, SB-3CT,4-Aminobenzoyl-Gly-Pro-D-Leu-D-Ala hydroxamic acid, keracyanin chloride,MMP2/MMP-9 Inhibitor I, MMP-2/MMP-9 Inhibitor II, MMP-9 Inhibitor I,MMP-9/MMP-13 inhibitor I, MMP-9/MMP-13 inhibitor II, MMP-2/MMP-9Inhibitor V, CP 471474, Ageladine A, TFA, or an equivalent of eachthereof. The above-listed MMP inhibitors are available from Abcam orSanta Cruz Biotech.

Also provided herein is a method of treating a subject with high bonemineral density, comprising administering an agent that increases theactivity of MMP-9 in the subject. In several aspects, the subject is amammal, e.g., a mouse, a canine, a feline, an ovine, a simian or a humanpatient. These methods can be used therapeutically or in veterinaryapplications, or alternatively, as an animal model to assay for newtherapies or treatments. The agents can be used alone or in combinationwith other known therapies. In some aspects, the subject has a bonerelated disease or condition selected from osteopetrosis,pycondysostosis, osteopoikilosis, meloreostosis, sclerosteosis, vanBuchem's disease, LRP5 high bone mass, LRP4 high bone mass,craniometaphyseal dysplasia, Camurati-Engelmann disease, Ghosalsyndrome, bone cancer, cancer metastasized to the bone, fluorosis, renalosteodystrophy, acromegaly, hepatitis C-associated osteosclerosis,myelofibrosis, mastocytosis, osseous tuberous sclerosis, Paget'sdisease, and SAPHO syndrome. Agents that increase MMP-9 activity in acell include, for example, recombinant or isolated MMP-9 protein andepidermal growth factor (see WO 2002/045740). In some aspects, the agentis selected from recombinant MMP-9, recombinant MMP-9 modified toinclude nuclear localization signals, a histone acetyltransferase enzymewith H3K18 specificity, and gene therapy with a polynucleotide encodingMMP-9.

Also provided is method to modulate H3NT proteolysis duringosteoclastogenesis in a cell, comprising, or alternatively consistingessentially of, or yet further consisting of, modulating the activity ofMMP-9 in the cell. In one aspect, H3NT proteolysis is increased byincreasing MMP-9 activity in the cell. Agents that increase MMP-9activity in a cell include, for example, recombinant or isolated MMP-9protein and epidermal growth factor (see WO 2002/045740). In anotheraspect, the H3NT proteolysis is decreased by depletion or inhibit ofMMP-9 activity in the cell. Agents that inhibit or decrease MMP-9activity are known in the art, e.g., as described in US Patent Appl. No.2017/0015647; 2013/0064878; and 2011/00114186, and incorporated hereinby reference. Cells that are suitably treated with the agents includewithout limitation a eukaryotic cell, a mammalian cell, e.g. a humancell, a equine cell, a canine cell, or a feline cell, an osteoclast, anosteoclast precursor, or a progenitor cell or stem cell capable ofdifferentiation into an osteoclast. Cells capable of differentiationinto an osteoclast include but are not limited to embryonic stem cells,induced pluripotent cells, hematopoietic stem cells, myeloid stem cells,granulocyte-macrophage colony forming unit (GM-CFU), monocyte precursor(CFU-M), progenitor cells, and pre-osteoclasts.

Descriptive Embodiments

Applicant discloses herein that MMP-9 is a novel H3NT protease requiredfor H3NT proteolysis observed during osteoclastogenesis. This datademonstrate that RANKL-induced differentiation of primary mouse OCPcells facilitates the progressive nuclear accumulation and activity ofMMP-9 concomitant with increased H3NT proteolysis. By applyingApplicant's novel ChIPac-Seq method, App licant determined that manycanonical osteoclastogenic genes are selectively targeted for H3NTproteolysis during osteoclastogenesis. Depletion of MMP-9 or inhibitionof MMP-9 activity abrogated H3NT proteolysis concurrent with impairedosteoclastogenic gene activation and defective osteoclastdifferentiation. Applicant's data support a model whereby RANKLsignaling induces MMP-9-dependent H3NT proteolysis at osteoclastogenicgenes to regulate their expression necessary for proficient osteoclastdifferentiation. Consistent with this, it has been demonstrated thatchemical inhibition of MMP-9 activity in vivo attenuates osteoclastformation in juvenile mouse clavaria and MMP-9−/− mice display delayedlong bone development and defective bone fracture repair (Vu et al.1998; Colnot et al. 2003; Cackowski et al. 2010; Franco et al. 2011).

Despite increasing evidence supporting H3NT proteolysis in epigeneticregulation, advances in the field have been significantly impeded by thelack of a method to define and investigate genomic regions targeted forH3NT proteolysis in mammalian cells. Applicant addresses this need byproviding a ChIP of acetylated chromatin (ChIPac) method as a generalapproach to map and examine H3NT-cleaved regions. Since H3K14 resideswithin the H3NT-cleaved fragment and primarily exists in either anunmodified or acetylated state in mammals, an H3K14ac-specific antibodywas used to selectively immunoprecipitate H3NT-containing nucleosomesfrom artificially acetylated crosslinked chromatin. ChIPac-Seq in MMP-9depleted OCP cells that lack H3NT proteolysis validated the proficiencyof the H3K14ac antibody to capture all nucleosomes, as the H3K14acenrichment patterns were nearly identical to H3CT control. Furthermore,ChIPac-Seq in control 3-day OCP-induced cells that exhibit limited H3NTproteolysis identified a small number of genomic regions displayingsignificant reductions in H3K14ac enrichment, indicative of nucleosomeslacking the H3NT. Inhibition of H3NT proteolysis in 3-day OCP-inducedcells rescued H3K14ac enrichment confirming that ChIPac with anH3K14ac-specific antibody identified sites selectively targeted for H3NTproteolysis during osteoclastogenesis. These results validate theChIPac-Seq method to identify H3NT-cleaved sites that, most likely, canbe utilized in other eukaryotic model systems. Application of ChIPac-Seqin this study resulted in the first demonstration of selective H3NTproteolysis at specific genomic sites during mammalian differentiation.

It was previously reported that proteolysis of the H3NT at genepromoters is directly correlated to transcriptional activation duringyeast sporulation (Santos-Rosa et al. 2009). In this report, ChIPac-Seqsimilarly identified H3NT-cleaved regions surrounding the TSS ofspecific protein coding genes during osteoclastogenesis. Whereas H3NTproteolysis occurred at yeast promoters, mouse preosteoclasts displayedH3NT-cleaved regions that partitioned as those that werepromoter-specific (P), coding region-specific (CR) or both (P+CR). Thefunctional significance for these differences, if any, is unclear.Regardless of H3NT cleavage location (P, CR or P+CR), the majority ofgenes targeted for H3NT proteolysis during osteoclast differentiationdisplayed concomitant significant changes in expression. H3NTproteolysis correlated to transcriptional activation for >82% of thesegenes during osteoclastogenesis, similar to results in yeast, supportingthe direct role of H3NT cleavage in gene activation. SeveralH3NT-cleaved genes were repressed and many others exhibited littledifference in expression during differentiation, suggesting that H3NTproteolysis regulates activation of specific groups of genes in acontext-dependent manner. In the context of RANKL signaling in OCPcells, the activation of a group of canonical osteoclastogenic genesnecessary for osteoclast differentiation was directly correlated to theselective H3NT proteolysis near their TSSs. Inhibition of H3NTproteolysis at these sites significantly impaired their activation,despite continuous RANKL signaling, resulting in defective osteoclastdifferentiation. Therefore, Applicant postulated that distinct signalingcues induce selective H3NT proteolysis to facilitate the rapidactivation of specific developmental genes necessary for proficientdifferentiation.

Biochemical purification of preosteoclast nuclear extracts identifiedMMP-9 as a novel H3NT protease. Detailed investigation confirmed thatMMP-9 is the principal histone protease in preosteoclasts thatselectively cleaves the H3NT in vitro and in cells. Applicant's resultsstrongly support a model whereby MMP-9 directly cleaves the H3NT toactivate genes. Without being bound by theory, Applicant does notexclude the possibility that MMP-9 activity may also regulate unknownfactors necessary to facilitate H3NT proteolysis and/or gene activationduring osteoclastogenesis. However, these results demonstrateproteolysis of histones by a metalloproteinase that, therefore, expandsthe spectrum of histone proteases beyond the canonical serine andcysteine protease families (Dhaenens et al. 2015). Also without beingbound by theory, these results suggest histone proteolysis by theremaining 22 MMPs. The primary P1 site of the yeast PRB1 serine proteaseand mouse Cathepsin cysteine proteases is H3A21 (Duncan et al. 2008;Duarte et al. 2014; Khalkhali-Ellis et al. 2014; Xue et al. 2014). Incontrast, in silico analysis predicted H3K18 as the primary P1 site forMMP-9, which was confirmed experimentally. The MMP-9 and PRB1endopeptidases generate a single major H3NT-cleaved product whereasCathepsins generate progressively shorter H3 forms after T22 due totheir additional aminopeptidase activity. These enzymatic and substratedifferences support MMP-9 as the founding member of a novel class ofH3K18 proteases.

Based on Applicants' findings and previous reports, Applicant looked todetermine if specific classes of H3NT proteases are utilized in acontext-dependent manner to facilitate distinct epigenetic mechanismsdue to their particular H3NT proteolytic activities. In the context ofmESC differentiation, the Cathepsin L H3A21 protease accumulates in thenucleus and is required for H3NT proteolysis (Duncan et al. 2008). Theresulting H3Δ22 cleaved product impeded CBX7 chromodomain binding toH3K27me3 in vitro suggesting that proteolysis of H3 aa1-21 reduces theaffinity of repressive H3K27me-binding proteins/complexes, thereby,facilitating gene activation in differentiating mESCs. This putativemechanism of epigenetic regulation may be conserved for H3A21 proteasesbut is less likely to apply to H3K18 proteases since an H3Δ18 peptidedid not impair H3K27me3-CBX7 binding in vitro (Duncan et al. 2008).Although the primary mechanism of epigenetic regulation by H3K18proteases remains unknown, the contrasting H3NT activities andepigenetic regulatory mechanisms observed between MMP-9 and Cathepsinsmay explain why each protease is selectively utilized duringdifferentiation of distinct cell types.

During osteoclast differentiation, MMP-9 accumulates in the nucleusconcomitant with gelatinase activity and H3NT proteolysis. Consistentwith the disclosed results, increasing evidence demonstrates MMP-9nuclear localization and activity in specific cell types and undercertain physiological conditions (Mannello and Medda 2012). Themechanisms that facilitate MMP-9 nuclear translocation remain unknownbut the lack of an NLS support the necessity of unidentifiedMMP-9-associated factors for transport. Applicant's results demonstratethat progressive MMP-9 nuclear accumulation during osteoclastogenesis isdirectly proportional to the extent of gelatinase activity and H3NTproteolysis. Robust gelatinase activity and H3NT proteolysis were notobserved prior to preosteoclast formation, despite nuclear localizationof the MMP-9 active form shortly after RANKL treatment, suggesting thata threshold of MMP-9 abundance regulates its nuclear protease activity.Furthermore, Applicant's results support H3K18 acetylation as a keyregulator of MMP-9 activity. The specific acetylation of H3K18 wasnecessary and sufficient for MMP-9 H3NT proteolysis of nucleosomesubstrates in vitro and, in preosteoclasts, the sites and extent of H3NTcleavage were directly proportional to the level of acetylated H3K18.These results demonstrating that H3NT proteolysis is dependent onCBP/p300 activity, but not other canonical H3K18 acetyltransferases,support CBP/p300 as a central regulator of H3K18ac-dependent H3NTproteolysis.

It was recently reported that CBP recruitment and histone acetylation atthe Nfatc1 promoter were directly correlated to Nfatc1 transcriptionalactivation during osteoclastogenesis, further supporting the necessityof CBP/p300-mediated H3K18 acetylation in regulating H3NT proteolysisand gene activation (Park-Min et al. 2014). Importantly, these resultsdemonstrate that the targeted acetylation of H3K18 at the H3NT cleavagesites of Nfatc1, Lif and Xpr1 was insufficient to induce theirexpression during osteoclastogenesis, supporting H3NT cleavage as aprerequisite for their activation. Without being bound by theory,modulation of H3NT proteolysis by H3K18 acetylation is a conservedregulatory mechanism of many H3NT proteases, as Cathepsin L activity wasalso augmented by H3K18ac in vitro (Duncan et al. 2008).

Previous reports demonstrated that other histone modifications alsoregulate the activity of H3A21 proteases. Methylation of H3K27 augmentedCathepsin L activity in vitro whereas acetylated H3K23 abrogated H3proteolysis in a dominant manner (Duncan et al. 2008). Similarly,H3K4me3 suppressed H3NT proteolysis in yeast consistent with the absenceof H3K4me3 in the cleaved H3NT peptides isolated from differentiatingmESCs (Santos-Rosa et al. 2009). In contrast to these reports,Applicant's results demonstrate that H3K4 methylation, H3K23 acetylationand H3K27 methylation are insufficient to regulate MMP-9 activity invitro. These findings suggest that distinct H3NT proteases aredifferentially regulated by a specific “histone code” that stimulates orinhibits their activity (Strahl and Allis 2000). This may explain, inpart, why only limited H3NT proteolysis is observed duringdifferentiation and why MMP-9-dependent H3NT proteolysis is detected atonly a small number of defined regions during osteoclastogenesis.

The H3NT proteases generate a cleaved H3 product that is transientlyretained in chromatin during yeast sporulation and mESC differentiation(Duncan et al. 2008; Santos-Rosa et al. 2009). Although the rapid H3NTproteolysis identified at yeast promoters was insufficient for geneactivation, the cleaved H3 facilitated subsequent nucleosome eviction atthese promoters, by unknown mechanisms, concomitant with theiractivation. These findings suggest the similar requirement of cleavedH3-mediated nucleosome eviction for proficient gene activation duringmammalian differentiation. However, Applicants' results demonstrate thatcleaved H3 is retained within chromatin of differentiated osteoclastsand that robust activation of the H3NT-cleaved genes examined duringosteoclastogenesis is independent of nucleosome eviction or histonereplacement near their TSSs. While retention of cleaved H3 is observedin chromatin of terminally differentiated and senescent cells, thefunctional significance between retention and eviction/replacement ofcleaved H3, as observed in differentiating mouse and human ESCs, remainsunknown (Duncan et al. 2008; Asp et al. 2011; Duarte et al. 2014;Vossaert et al. 2014).

Experimental Details Proteolysis of the Histone H3 N-Terminal TailDuring Osteoclastogenesis

Since the epigenetic mechanisms that regulate mammalianosteoclastogenesis are largely unknown, an established ex vivo cellmodel was used to examine possible histone PTM changes duringdifferentiation. Primary osteoclast precursor (OCP) cells derived fromadult mouse long bone were cultured with the osteoclastogenic factorRANKL to induce synchronous osteoclast differentiation (An et al. 2014).As shown in FIG. 1A, nearly all 3-day OCP-induced cells were mononuclearpreosteoclasts that fuse to form large multinuclear osteoclasts by day5. Nuclei were isolated from OCP-induced cells at these time points andchromatin was extracted. Western blot analysis revealed an unexpecteddifferentiation-dependent fast-migrating H3 band in chromatin ofpreosteoclasts with elevated levels detected in osteoclasts (FIG. 1B).Because an H3 C-terminal (H3CT) antibody was used in the Western blotanalysis, the observed fast-migrating H3 band indicates specificproteolysis of the H3 N-terminal (H3NT). Fast-migrating bands of othernucleosome core histones were not observed demonstrating the selective,but limited, proteolysis of the H3NT during osteoclastogenesis (FIG.1B).

MMP-9 is the Principal H3NT Protease in Preosteoclasts

To identify the protease responsible for H3NT cleavage observed inpreosteoclasts, nuclear extracts from 3-day OCP-induced cells werefractionated by a series of chromatography steps (FIG. 1C). An in vitroH3NT cleavage assay was developed using a recombinant H3 (rH3) substrateand Western blot analysis with the H3CT antibody to track and isolatenuclear fractions containing H3NT protease activity. Initialfractionation by P11 chromatography revealed that H3NT protease activitywas largely restricted to two sequential fractions, BC400 and BC500,suggesting that a single protease cleaves the H3NT in preosteoclasts.These fractions were combined and fractionated on a Q-sepharose columnwhere, again, H3NT protease activity was largely restricted to twosequential fractions, BR100 and BR200. The fractions were combined forglycerol gradient sedimentation resulting in the final purification offractions (#3-5) containing H3NT protease activity. These purifiedfractions were initially incubated with different protease inhibitors toidentify the family of proteases responsible for H3NT cleavage. Variousserine and cysteine protease inhibitors failed to inhibit H3NT proteaseactivity, which was highly unexpected as these families were reported toproteolyze the H3NT in yeast and mice, respectively (FIG. 1D) (Duncan etal. 2008; Khalkhali-Ellis et al. 2014; Xue et al. 2014). Furtherscreening demonstrated that only metalloproteinase inhibition couldabrogate H3NT cleavage activity (FIG. 1E). Consistent with theseresults, proteomic analysis of the purified fractions revealed thatmatrix metalloproteinase 9 (MMP-9) was the predominant of the four knownproteases identified (FIG. 1F). In vitro H3NT cleavage assays usingthese recombinant proteases demonstrated that only rMMP-9 possessed H3NTprotease activity (FIG. 1G). The purified fractions and rMMP-9 displayedsimilar H3NT protease activities for octamer and nucleosome arraysubstrates as well as for H3.1, H3.2 and H3.3 substrates (FIGS. 8A-8B).Incubation of the purified fractions with a selective MMP-9 inhibitorabolished H3NT proteolysis confirming that MMP-9 activity is requiredfor H3NT cleavage in vitro (FIG. 1E). These findings identify MMP-9 as anovel H3NT protease and the principal H3NT protease in preosteoclasts.

MMP-9 Activity is Required for H3NT Proteolysis DuringOsteoclastogenesis

Matrix metalloproteinases are a large diverse family of zinc-dependentendopeptidases that function to remodel the pericellular space viaproteolysis of extracellular matrix proteins (Nagase et al. 2006). MMP-9and MMP-2 comprise the gelatinase sub-family of MMPs and aredifferentially expressed in osteoclasts and osteoblasts, respectively.MMP-9 is synthesized as an inactive/latent 92-kDa proenzyme andsubsequently converted to an 82-kDa active form by proteolysis of itsinhibitory N-terminal prodomain. Since MMP-9 is a secretory protein,Applicants' results demonstrating nuclear MMP-9 activity wereunexpected. To address this discrepancy, MMP-9 localization dynamicswere examined during osteoclastogenesis. Western blot analysisdemonstrated that MMP-9 was absent in control OCP cells but both thepro- and active-forms of MMP-9 were detected in the nuclear compartmentof 1-day OCP-induced cells (FIG. 2A and FIG. 9A). MMP-9 proteinabundance was maximal by day 3 post-induction and was sustained in 5-dayOCP-induced cells. Immunofluorescence microscopy confirmed theprogressive nuclear accumulation of MMP-9 in OCP-induced cells (FIG.9B). Gelatin zymography was performed using nuclear extracts isolatedfrom OCP-induced cells to assess nuclear-specific MMP-9 gelatinaseactivity. Nuclear gelatinase activity mirrored the progressive nuclearaccumulation of MMP-9 during osteoclastogenesis (FIG. 2B). These resultsindicate that maximal MMP-9 nuclear abundance and activity observed in3-day OCP-induced cells directly correlate with H3NT proteolysis. Totest the dependence of H3NT cleavage on MMP-9 during osteoclastogenesis,OCP cells were transduced with a control or MMP-9-specific shRNA todeplete MMP-9 prior to induction (FIG. 2C). MMP-9 depletion impedednuclear gelatinase activity in OCP-induced cells concurrent with thesignificant and sustained impairment of H3NT proteolysis (FIGS. 2B and2D). The continuous impairment of H3NT cleavage was similarly observedin OCP-induced cells treated with a selective MMP-9 inhibitor (FIG. 2D).These collective results support the dependence of H3NT proteolysis onnuclear MMP-9 activity during osteoclastogenesis.

H3K18 is the Primary P1 Site of MMP-9

Previous reports demonstrated that H3A21 is the primary cleavage site(P1) for cysteine and serine proteases, however, the H3NT P1 site of theMMP-9 metalloproteinase was unknown (Duncan et al. 2008; Santos-Rosa etal. 2009). In silico analysis of histone H3 identified K18 as the onlypotential P1 site on the H3NT, which was also predicted to be cleaved byMMP-9 (FIG. 10A) (Song et al. 2012). To test these predictions, LC-MS/MSof the gel-excised rH3-cleaved product generated by rMMP-9 was performed(FIG. 3A). Peptide fragments containing H3 residues prior to Q19 werenot identified in the proteomic analysis, supporting H3K18 as the majorP1 site of MMP-9. This result suggested that the sequence flanking H3K18is a putative MMP-9 consensus site. To test this in vitro, rH3containing mutated residues predicted necessary for MMP-9 activity wereused as substrates in the H3NT cleavage assay (FIG. 3B and FIG. 10B).Mutation of rH3 at (P1, K18R; P1′, Q19G) or flanking (P3, P16G; P3′,A21F) the cleavage site ablated H3NT proteolysis by rMMP-9, confirmingthat the H3 aa16-21 sequence is an MMP-9 consensus site in vitro (FIG.3C). These results suggested that similar H3 mutations would ablate H3NTproteolysis during osteoclastogenesis. To test this, C-terminal FLAG-tagfusions of wild type H3 or the H3 mutants were transduced in OCP cellsprior to induction. Western blot analysis of chromatin extractsconfirmed proteolysis of wild type H3-FLAG in OCP-induced cells (FIG.3D). Although mutant H3-FLAG proteins were also readily detected inchromatin extracts, each mutation of the MMP-9 consensus sequenceabrogated H3NT proteolysis in OCP-induced cells. These findings supportMMP-9 as the primary protease that directly cleaves H3K18-Q19 duringosteoclastogeneis.

Acetylation of H3K18 Augments MMP-9 Activity

Analysis of the canonical MMP-9 consensus sequence indicated that MMP-9preferentially cleaves uncharged residues over charged residues at theP1 site (FIG. 10B). Based on this, Applicants hypothesized thatneutralizing the H3K18 charge by acetylation would augment MMP-9activity. As predicted, kinetic analysis of MMP-9 activity using H3peptide substrates confirmed that K18ac selectively amplified rMMP-9activity resulting in a 3-fold increase of cleaved H3 compared tounmodified H3 or H3K27me1 peptides (FIG. 4A). Consistent with theseresults, H3NT cleavage assays using rH3 acetyl-lysine analogues assubstrates demonstrated that the specific acetylation of K18 robustlyincreased H3NT proteolysis by rMMP-9 (FIG. 4B) (Shogren-Knaak andPeterson 2004). MMP-9 activity with rH3 methyl-lysine analogues at K4,K9, K27 or K36 was nearly identical to rH3 control in all cases (FIG.11A). These findings suggested that the acetylation of H3K18 facilitatesMMP-9 activity in chromatin. To test this, nucleosome arrays containingunmodified rH3, the rH3 acetyl-lysine analogues or modified nativehistones purified from HeLa cells were generated in vitro and used assubstrates in the H3NT cleavage assay (Kim et al. 2013a). Remarkably,unmodified nucleosome array substrates were completely resistant torMMP-9 protease activity, in contrast to unmodified rH3 and octamersubstrates (FIGS. 4B-4C and FIG. 8). Conversely, rMMP-9 displayed robustactivity for modified native nucleosome arrays supporting the dependenceof MMP-9 H3NT protease activity on specific histone PTMs in chromatin(FIG. 4C). Consistent with this, H3NT cleavage assays confirmed that thespecific acetylation of H3K18 was both necessary and sufficient for H3NTcleavage by rMMP-9 in a nucleosome array context (FIG. 4B). Theseresults suggested that acetylation of H3K18 was required forMMP-9-dependent H3NT cleavage during osteoclastogenesis. To test this,OCP cells were transduced with a control shRNA or an shRNA to depletethe CBP/p300 acetyltransferases, which are responsible for the majorityof H3K18ac, prior to induction (Henry et al. 2013). Diminishment ofH3K18ac in CBP/p300 depleted OCP-induced cells resulted in the sustainedimpairment of H3NT proteolysis without perturbing the nuclear abundanceof active MMP-9 (FIGS. 4D-4E). Identical results were obtained fromOCP-induced cells treated with a selective CBP/p300 inhibitor (FIG. 4E).Depletion of the known H3K18 acetyltransferases GCN5, Tip60 or MOZ didnot impair H3NT proteolysis during osteoclastogenesis, in contrast toCBP/p300 depletion (FIGS. 11B-11C). These collective results support theregulation of MMP-9-dependent H3NT cleavage during osteoclastogenesis bythe CBP/p300-mediated acetylation of H3K18.

MMP-9 is Required for Osteoclastogenic Gene Activation and ProficientOsteoclastogenesis

It was previously reported that H3NT cleavage facilitates geneactivation in yeast during sporulation, suggesting that MMP-9-dependentH3NT proteolysis similarly functions in gene activation duringosteoclastogenesis (Santos-Rosa et al. 2009). To test this, Applicantssought to identify the genes regulated by MMP-9 using RNA-Seq of totalmRNA isolated from control or MMP-9 depleted 3-day OCP-induced cells(FIG. 2C). Comparative transcriptome analysis revealed 1,131differentially expressed genes between the samples (Table 1 and FIGS.12A-12B). More than 67% of these genes displayed significantly reducedexpression in MMP-9 depleted cells, supporting a function for MMP-9 ingene activation during osteoclastogenesis (FIG. 5A). Gene ontologyanalysis revealed that many of these genes are regulatory components ofosteoclastogenic signaling pathways including the RANKL, AMPK and VEGFpathways (FIG. 12C). In addition, gene set enrichment analysis (GSEA)demonstrated that the expression of a large set of RANKL and boneremodeling pathway genes was significantly reduced in MMP-9 depletedcells compared to control cells (FIG. 5B). Examination of theleading-edge subset of these genes identified 26 canonicalosteoclastogenic genes that required MMP-9 for their activation,including Nfatc1, Lif and Xpr1 (FIG. 5C) (Takayanagi et al. 2002; Bozecet al. 2008; Sharma et al. 2010). Importantly, the diminished H3NTcleavage and defective osteoclastogenic gene activation observed inMMP-9 depleted or inhibited 5-day OCP-induced cells were concurrent witha significant reduction of mature osteoclasts compared to control cells(FIG. 5D and FIG. 12D). Similar results obtained from CBP/p300 depletedor inhibited 5-day OCP-induced cells further support the dependence ofosteoclastogenic gene activation and proficient osteoclastdifferentiation on H3NT proteolysis (FIG. 5D and FIG. 12D).

ChIPac-Seq: A Novel Approach to Identify H3NT-Cleaved Regions

The results suggested that MMP-9-dependent H3NT proteolysis directlyregulates gene expression during osteoclastogenesis but the possibleindirect effects of MMP-9 depletion on gene expression, independent ofH3NT cleavage, could not be distinguished by transcriptomic analysis.Therefore, Applicants sought to determine the genomic sites targeted forH3NT proteolysis during osteoclastogenesis to directly investigate therole of H3NT cleavage in transcriptional regulation, however, a methodto identify H3NT-cleaved sites in mammalian cells has not been reported.Applicants hypothesized that mapping these sites could be achieved bycomparative ChIP-Seq analysis of the H3NT between control and MMP-9depleted 3-day OCP-induced cells that exhibit or lack H3NT cleavage,respectively (FIG. 2D). Computational identification of genomic regionsdisplaying significantly reduced H3NT enrichment in control versus MMP-9depleted cells would indicate those regions selectively targeted forH3NT proteolysis during osteoclastogenesis. This ChIP approach requiresan antibody that has specific affinity for the H3NT of all H3 proteins,is not dependent on or inhibited by existing H3 PTMs and is validatedfor ChIP applications, however, such an antibody is currentlyunavailable to the best of Applicants' knowledge. To bypass thistechnical barrier, established biochemical techniques were utilized todevelop a novel method, called ChIP of acetylated chromatin (ChIPac),for identification and examination of H3NT-cleared regions (FIG. 6A).Applicants reasoned that an H3K14 acetyl-specific antibody satisfies thecriteria above for ChIP of the H3NT following complete lysineacetylation of crosslinked chromatin in vitro by acetic anhydride.First, cells were fixed with methylene blue to crosslink chromatin afterbrief exposure to white light (Tuite and Kelly 1993). Becauseformaldehyde reacts with lysine e-amino side-chains, which likelyprecludes complete lysine acetylation by acetic anhydride, methyleneblue was used as an alternative for cell fixation (Metz et al. 2004).Chromatin was isolated and the efficiency of crosslinking was confirmedby SDS-CIA prior to sonication (FIG. 13A) (Lalwani et al. 1990).Fragmented chromatin was then treated with acetic anhydride tocompletely acetylate all unmodified lysine residues in vitro (FIG. 13B)(Nakayasu et al. 2014). ChIPac using an H3K14 acetyl-specific antibodyselectively enriched H3NT-containing chromatin and simultaneouslyexcluded chromatin lacking the H3NT. ChIPac using an H3CT antibody wasperformed in parallel as the normalization control. H3NT-cleaved regionswere identified by the significant reduction in H3K14ac enrichmentrelative to control as determined by qPCR or NextGen sequencinganalysis.

Specific Gene TSSs are Targeted for H3NT Proteolysis DuringOsteoclastogenesis

ChIPac-Seq was performed using control and MMP-9 depleted 3-dayOCP-induced cells to identify the specific sites targeted for H3NTproteolysis during osteoclastogenesis. MMP-9 depleted cells that lackH3NT-cleaved chromatin displayed nearly indistinguishable enrichmentpatterns between H3K14ac and H3CT control, as predicted (FIG. 6B andFIGS. 13C-13D). These important results validated the ChIPac approach topurify all H3NT-containing chromatin using the H3K14ac-specificantibody. The capability of ChIPac-Seq to identify specific H3NT-cleavedregions was confirmed in control 3-day OCP-induced cells, which resultedin the identification of 1,233 regions displaying significantly reducedH3K14ac enrichment relative to MMP-9 depleted cells. The maximal peak ofH3K14ac depletion within each H3NT-cleaved region and the gene nearestthis peak were determined (Table 2) (Kim et al. 2013b). Applicant'ssubsequent computational analyses focused on the +/−4 kb region neargene transcription start sites (TSSs) since H3NT cleavage was previouslyreported at gene promoters in yeast (Santos-Rosa et al. 2009). K meansclustering of TSSs revealed that <8% of all protein coding genesexhibited H3K14ac depletion near TSS indicating that these sites areselectively targeted for H3NT proteolysis during osteoclastogenesis(FIG. 6B and FIGS. 13C-13D). Strikingly, these genes partitioned intothree distinct groups based on the location of H3NT cleavage:promoter-specific (P, 31%), coding region-specific (CR, 42%) or both(P+CR, 27%). Profiling the average tag densities in each group showedthat H3NT cleavage typically peaks ˜2 kb from TSS (FIG. 6C). Genepathway analysis indicated that H3NT-cleaved genes are significantlylinked to the RANKL and bone remodeling pathways (FIG. 13E). Severalcanonical osteoclastogenic genes were identified within eachH3NT-cleaved group, including Nfatc1 (P), Lif (CR) and Xpr1 (P+CR).Notably, MMP-9 was required for H3NT cleavage near Nfatc1, Lif and Xpr1TSSs and their concurrent activation during osteoclastogenesis,suggesting that H3NT proteolysis facilitates gene activation (FIG. 13C).

H3NT Cleavage Correlates with Gene Activation

To broadly examine the association between H3NT cleavage and geneexpression, the RNA-Seq data was analyzed for the 1,233 H3NT-cleavedgenes identified in control and MMP-9 depleted 3-day OCP-induced cells.Comparative analyses revealed that most H3NT-cleaved genes (>53%)displayed significant expression differences in control versus MMP-9depleted cells (FIG. 7A). The majority of these genes (>82%), includingNfatc1, Lif and Xpr1, exhibited significantly reduced expression inMMP-9 depleted cells indicating a strong functional correlation betweenMMP-9 and gene activation (FIG. 7A). To further investigate theMMP-9-dependent activation of these genes during osteoclastogenesis,RT-qPCR was performed in OCP cells transduced with a control orMMP-9-specific shRNA, or treated with DMSO control or a selective MMP-9inhibitor, and cultured with or without RANKL for 3 days. Ablation ofH3NT cleavage in MMP-9 depleted or inhibited 3-day OCP-induced cellssignificantly impaired Nfatc1, Lif and Xpr1 activation, suggesting thatH3NT proteolysis directly facilitates their activation duringosteoclastogenesis (FIGS. 2D, 7B and FIG. 14). Applicants reasoned thatrepeating these experiments in CBP/p300 depleted or inhibited 3-day OCPcells would test this hypothesis, as non-acetylated H3K18 impedes MMP-9H3NT protease activity (FIG. 4). Consistent with the hypothesis,diminishment of H3K18 acetylation by CBP/p300 depletion or inhibitionablated H3NT cleavage and significantly impaired Nfatc1, Lif and Xpr1activation, identical to the effects of MMP-9 depletion, but withoutaltering nuclear abundance of the active MMP-9 enzyme (FIGS. 4D-4E, 7Band FIG. 14). These results further support the direct function of H3NTcleavage in gene activation and suggest that CBP/p300-mediatedacetylation of H3K18 is a key regulator of MMP-9 H3NT protease activityduring osteoclastogenesis.

The Sites and Extent of H3NT Proteolysis are Directly Linked to H3K18Acetylation

Identification of the specific H3NT-cleaved sites at Nfatc1 (P), Lif(CR) and Xpr1 (P+CR) allowed us to directly examine the necessity ofH3K18 acetylation on MMP-9 H3NT protease activity and gene activationduring osteoclastogenesis. OCP cells were transduced with a control,MMP-9-specific or CBP/p300-specific shRNA, cultured with or withoutRANKL for 3 days and then processed for ChIPac or conventional ChIPusing an H3K18ac-specific antibody. Subsequent qPCR confirmed thesite-specific H3NT cleavage at Nfatc1 (P), Lif (CR) and Xpr1 (P+CR) ininduced versus non-induced control shRNA cells (FIG. 7C). In contrast,H3K18ac enrichment at all sites examined were remarkably similar betweeninduced and non-induced control shRNA cells (FIG. 7D). These results andthe findings above suggested that H3NT cleavage sites are selectivelytargeted for H3K18 acetylation to activate MMP-9 H3K18-Q19 proteolysis,resulting in a tailless H3 that is exempt from enrichment by the H3K18acChIP. Consistent with this model, significantly increased H3K18acenrichment at each H3NT cleavage site, but not the flanking non-cleavagesites, was concurrent with the ablation of H3NT cleavage at these sitesin MMP-9 depleted 3-day OCP-induced cells (FIGS. 7C-7D). Notably, therelative increase of H3K18ac at each H3NT cleavage site observed inMMP-9 depleted cells was directly proportional to the relative decreaseof H3K14ac observed in control shRNA cells, suggesting that H3K18acetylation directly regulates the sites and extent of MMP-9 H3NTprotease activity during osteoclastogenesis. Consistent with this,preclusion of H3K18 acetylation at each H3NT cleavage site wasconcurrent with the loss of H3NT cleavage at these sites in CBP/p300depleted 3-day OCP-induced cells, despite the presence of active MMP-9in the nucleus (FIGS. 4D and 7C-7D). The collective results indicatethat the targeted CBP/p300-dependent acetylation of H3K18 at Nfatc1 (P),Lif (CR) and Xpr1 (P+CR) is prerequisite but insufficient for theirexpression, thereby, further supporting the necessity of H3NTproteolysis for their activation during osteoclastogenesis.

Cell Transduction and Inhibition

Retroviral particles were generated in Plat-E cells transfected withpMX-H3-Flag (Cell Biolabs) according to the manufacturers' instructions.Lentiviral particles were generated in HEK-293T cells by co-transfectingplasmids encoding VSV-G, NL-BH and pLKO.1-shRNA (Addgene) for MMP-9(5′-GAGGCATACTTGTACCGCTAT (SEQ. ID NO: 19), p300(5′-CCCTGGATTAAGTTTGATAAA (SEQ ID NO: 20)) or CBP(5′-TAACTCTGGCCATAGCTTAAT (SEQ ID NO: 21)). OCP cells were transducedand selected with puromycin (2 μg/ml) or cultured with DMSO, 10 nMMMP-9-INI (Santa Cruz) or 1.6 μM C646 (ApexBio) for 3 days prior todifferentiation.

Chromatin Extraction and Western Blot Analysis

Chromatin was extracted by first resuspending cells in buffer A (10 mMHEPES, pH 7.4, 10 mM KCl, 1.5 mM MgCl2, 0.34 M sucrose, 10% glycerol, 1mM DTT, 5 mM β-glycerophosphate, 10 mM NaF, protease inhibitors, and0.2% Triton X-100) and incubating on ice for 8 min. Nuclei were isolatedby centrifugation (1,300 g for 10′ at 4° C.), resuspended in buffer B (3mM EDTA, 0.2 mM EGTA, 1 mM DTT, 5 mM β-glycerophosphate, 10 mM NaF, andprotease inhibitors), centrifuged (1,700 g for 5 min at 4° C.) and thechromatin pellet was washed three times with buffer B prior tosonication in Laemmli buffer. Western blot analysis was performed usingantibodies specific for H2A, H2B, H3 and H4 (Abcam); H3K9ac, H3K14ac,H3K18ac and H3K23ac (Active Motif); MMP-9, p300 (Santa Cruz) and CBP(BioLegend); His (Novagen) and FLAG (Sigma).

Recombinant Proteins and H3 Cleavage Assays

His-tagged proteins were generated in Rosetta 2 (DE3) pLysS E. coli(Novagen) and purified as previously described (Kim et al. 2008). MMP-9(aa115-730) was purified from inclusion bodies dissolved with lysisbuffer (6 M urea, 0.5 M NaCl, 5 mM imidazole, 20 mM Tris, pH 7.9),refolded in 50 mM HEPES, 0.2 M NaCl, 1M NDSB201 (Sigma) and dialyzed in50 mM Tris, pH 7.5, 0.1 M NaCl, 5 mM CaCl2, 20 uM ZnCl2 and 30%glycerol. Recombinant and native histone octamers and nucleosome arrayswere prepared as previously described (Kim et al. 2012). Cell extractsor recombinant proteins were incubated with histone octamer (1 μg) ornucleosomes (2 μg) in cleavage buffer (20 mM HEPES-KOH, pH 7.8, 1 mMCaCl2, 20 mM KCl) for 0.5-2 hours at 37° C.+/−protease inhibitorsaprotinin (10 μg/ml), bestatin (130 μm), EDTA (25 mM), leupeptin (100μM), pepstatin A (1.5 μM), PMSF (1 mM) or L006235 (20 nM). H3 tailpeptides (aa10-35) were synthesized by solid-phase Fmoc/tBu chemistryand purity confirmed by ES-MS (EZBiolab). Peptides were incubated withrMMP-9 at seven different concentrations (0, 25, 50, 100, 150, 200, and250 μM) in cleavage buffer, the reactions stopped by adding 20 mMo-phenanthroline (Sigma) and peptide hydrolysis was measured by adding 5mM fluorescamine followed by detection at λ_(ex) 365 nm and λ_(em) 450nm using a Plate Chameleon spectrofluorometer (Hidex). Kineticparameters were determined by Michaelis-Menten analysis.

Chromatography

Nuclear extracts were fractionated on a P11 column (Pharmacia)equilibrated with BC100 buffer (20 mM HEPES-KOH, pH 7.9, 0.5 mM EDTA,0.05% Nonidet P-40, 10% glycerol, 1 mM DTT, 100 mM KCl) as previouslydescribed (Kim et al. 2013b). H3NT active fractions were combined anddialyzed against Buffer R (10 mM HEPES-NaOH, pH7.6, 10 mM KCl, 1.5 mMMgCl2, 10% glycerol, 10 mM β-glycerophosphate, 1 mM DTT), loaded onto aQ-Sepharose column (Phamacia) and eluted with stepwise increased saltconcentration in BR buffer. H3NT active fractions were combined andapplied to a 5-ml 15-40% glycerol gradient in BR200 buffer containing0.1% Nonidet P-40, centrifuged in an SW 55Ti rotor (150,000 g for 20hours at 4° C.) and fractions (150 μl) were collected from the top ofthe tube. H3NT active fractions (#3-5) were combined for proteinidentification by LC-MS/MS analysis.

RNA-Seq

RNA Isolation and Library Preparation.

RNA was prepared using the Qiagen RNeasy kit (Qiagen, Valencia, Calif.)according to the manufacturer's instructions. For quality control, RNApurity and integrity were verified by denaturing gel electrophoresis, OD260/280 ratio, and analysis on an Agilent 2100 Bioanalyzer (AgilentTechnologies, Santa Clara, Calif.). Strand specific library perpetrationwas carried out using a KAPA Stranded mRNA-Seq Kit, with KAPA mRNACapture Beads (KAPA Biosystem Wilmington, Mass.). Briefly, 30 ng oftotal RNA was reverse transcribed to cDNA using a T7 oligo(dT) primer.Second-strand cDNA was synthesized, in vitro transcribed, and labeledvia incorporation of biotin-16-UTP. Validation of the librarypreparations was performed on an Agilent Bioanalyzer using the DNA1000kit. Libraries were quantified using a Roche LightCycler96 withFastStart Essential DNA Green Master mix. Library concentrations wereadjusted to 4 nM and pooled for multiplex sequencing. Pooled librarieswere denatured and diluted to 15 pM and then clonally clustered onto thesequencing flow cell using the Illumina cBOT Cluster Generation Stationand Cluster Kit v3-cBot-HS. The clustered flow cell was sequenced with1×50 SE reads on the Illumina HiSeq2000 according to manufacturer'sprotocol. Base conversion was made using OLB version 1.9, de-multiplexedand converted to Fastq using CASAVA version 1.8 (Illumina). Thisresulted in approximately 50 million reads for control and MMP-9 shRNAexpressing OCP cells. The library preparation and sequencing wereperformed in conjunction with the Sequencing Core Facility of UCLA, LosAngeles.

Bioinformatic Analyses of RNA-Seq.

To check the general quality of raw sequencing reads, Applicants usedin-house RNA-seq workflow (University of Southern California, EpigenomeCenter) which consists of several open source tools. Briefly, to checkthe quality of sequencing reads in FastQC, reads were trimmed on bothends based on quality score (>38) of each sequence by usingFASTX-Toolkit (http://hannonlab.cshl.edu). Adaptor sequences were alsoremoved. High quality reads were aligned to the mm9 genome usingTopHat-2 which uses Bowtie 2 at different steps, allowing one mismatch(in conjunction with gene model from Ensembl release 61) (Kim et al.2013a). Potential PCR duplicated reads identified with theMarkDuplictaes using Picard (https://github.com) were excluded. Furtheralignment quality was checked using SamStat (Lassmann et al. 2011),RNA-seQC (DeLuca et al. 2012), Seqmonk, IGV and Qualimap (Garcia-Alcaldeet al. 2012). A total of approximately 21 million unique mapped readsfor each control and MMP-9 shRNA expressing OCP cells were obtained.

Transcript coverage. Applicants used coverage over the transcript plotsto identify any problems associated with library preparation, sequencingprocess and distribution of reads across the genome or any bias in 5′ or3′ expression using Qualimap and RNA-seQC packages. The majority of thereads (>80%) of all samples were within exonic regions and very lownumber of reads mapped to intronic or intergenic regions (FIG. 12A). Toinvestigate any 5′ or 3′ bias in the expression, intronic positions wereremoved, coverage vectors for minus-strand genes were reversed, andremaining values divided into 100 non-overlapping bins were averaged toproduce a uniform 100-column matrix of gene coverage for each sample.Genes <100 bp were not included in the analysis. Gene-wise trends incoverage bias and variability were studied by taking the coefficient ofvariance of the original coverage vector per gene and that of the ratioof the first-quarter mean depth (5′ coverage) to fourth-quarter meandepth (3′ coverage) on the gene body. Global coverage bias per samplewas plotted against normalized coverage (FIG. 12B) as detailedpreviously (Graw et al. 2015). To obtain an overall robust geneexpression, Applicants used an exon model by counting all reads mappedto only exons and combining all exons to a gene so that Applicants haveread count per gene (RPKM) (Mortazavi et al. 2008). The RPKM values wereadjusted globally by matching count distributions at the 75th percentileand then adjusting counts to a uniform distribution between samples.Finally differential expression was estimated by selecting transcriptsthat displayed significant changes (p<0.05) after Benjamini and Hochbergcorrection using a null model constructed from 1% of transcripts showingthe closet average level of observation to estimate experimental noise(Ring et al. 2015). The gene list was further ranked using fold changecriteria. GSEA and leading edge analyses were performed on the rankedlist using gene sets from the C2 collection of the GSEA MolecularSignatures Database v3.0 and several gene sets associated with boneremodeling as detailed previously (Kim et al. 2015).

ChIPac-Seq

ChIP-ac.

Cells were fixed with 10 μM methylene blue (Sigma) on ice and exposed towhite light from a 100 W incandescent bulb at a distance of 3 cm for 3′.Crosslinking was confirmed by SDS-chloroform-isoamyl alcohol (SDS-CIA)of extracted chromatin prior to dialyzation against acetylation buffer(50 mM NaHCO3, pH 8.0, 150 mM NaCl, 0.01% SDS). Chromatin was acetylatedwith acetic anhydride (20 mM final) in an ice-bath for 1 h whilemaintaining the pH at 8.0-8.2 by addition of NaOH. Acetylated chromatinwas immunoprecipitated with an H3K14ac-specific antibody (Active Motif)or an H3 C-terminal (H3CT) antibody (Abcam) as previously described (Kimet al. 2015).

Library Preparation.

DNA libraries were constructed from ˜30 ng of DNA obtained from eachChIP sample. ChIP DNA and input DNA were first band-isolated on a 2%agarose gel to obtain fragments between 150 and 350 base pairs and DNAwas extracted using the QIAquick gel extraction kit (Qiagen) and elutedin 35 μL elution buffer. For input, DNA was diluted 1:5 after gelextraction. The DNA was end-repaired and adapters were ligated tosamples for 15 min at room temperature. Adapters in excess wereeliminated by gel purification on a 2% agarose gel. A final sizeselection was performed using a 2% agarose gel to obtain a library witha median length of ˜230 bp which is within the recommended size rangefor cluster generation on Illumina's flow cell. Following PCR, reactionswere cleaned using magnetic beads and resuspended in a small volume of10 mM Tris 8.5 (Qiagen EB). Libraries were visualized by AgilentBioanalyzer and quantified using the KAPA Biosystems LibraryQuantification Kit, according to manufacturer's instructions. Sequencingwith 1×50 SE reads was carried out on the Illumina flow cell of HiSeq2000 as recommended by manufacturer (Illumina). Image analysis and basecalling were carried out using RTA 1.13.48.0. Final file formatting,de-multiplexing and fastq generation were carried out using CASAVA v1.8.2.

ChIPac-Seq Quality Assessment.

All ChIP and input sample qualities were monitored using establishedstrategies (Landt et al. 2012; Bailey et al. 2013). The quality matricesfor raw sequence reads were obtained by FASTQc(http://www.bioinformatics.bbsrc.ac.uk). The reads were processed byTrim Galore (http://www.bioinformatics.babraham.ac.uk). The lowsequencing quality nucleotides at the 3′ end were removed, and only thereads longer than 75 bp were retained. Adaptor sequences were alsoremoved using function cutadapt. The processed sequences were mapped tothe mm9 genome using Burrows-Wheeler Aligner (Li et al. 2008). Furtherreads aligning to mitochondrial DNA, repetitive elements or unassignedsequences were discarded. This resulted in uniquely aligned reads fromapproximately 13 to 34 million reads covering the mouse genome.Applicants used deeptools (https://pypi.python.org/pypi/deepTools) toestimate distribution of ChIP signal from background noise(function-bamFingerprint) and cross-sample normalization was achieved byscaling read depths to reads using function-bamCoverage. Since the DNApolymerases, used in PCR-amplifications during the library preparation,prefer GC-rich regions and may influence the outcome of the sequencing,the GCbias was estimated in each sample but no correction was applied(data not shown). To validate the ChIPac-Seq approach, afunction-bamFingerprint was used on uniquely mapped reads, whichrandomly samples genome regions into a specified length (10 bp bin) andcounts the reads from indexed barn files that overlap with thoseregions. These counts were then sorted according to their rank (the binwith the highest number of reads will have the highest rank) and thecumulative sum of read counts was plotted (Diaz et al. 2012). In allcases it is possible to differentiate read density of the ChIPac samplefrom the input sample.

Establishment of Reference Loci.

To calculate the differential tag density of each ChIPac sample,Applicants used a binning approach (Diaz et al. 2012). Applicantsnormalized tag density to 1× coverage to compensate for the varyingsequencing depth and mapping efficiency of each sample. Suchnormalization is achieved by first determining the actual read coverage(number of mapped reads*fragment length/effective genome size) and thenusing this number to determine the scaling factor that would yield a 1×coverage, as previously detailed (Kramer et al. 2011). Since each shortread represents the end of an immunoprecipitated nucleosome, every readwas extended 3′ to a total of 200 bp to cover an entire nucleosome priorto analysis. Signal density was calculated in sliding 1 kb windows andnormalized aligned reads were considered to be within a window of themidpoint of its estimated fragment. Mid-points in each window werecounted, and empirical distributions of window counts were created.Genomic bins containing statistically significant regions wereidentified by comparison to a Poisson background model assuming thatbackground reads are spread randomly throughout the genome (Kim et al.2013c).

Identification and Analyses of H3NT-Cleaved Genes.

Applicants extracted the tag density in a ±4 kb window surrounding theTSSs using the program ngs.plot (https://github.com) (Shen et al. 2014)and Seqminer (Ye et al. 2011). To identify H3NT-cleaved regions inspecific genomic loci, relative signal densities were defined as readcounts per bin fixed divided by the total number of aligned reads in allbins. The loci which displayed differential read count in 1 kb windowsbetween control shRNA H3K14ac over H3CT, as well as MMP-9 shRNA samples(H3K14ac and H3CT) with log₂ ratio >0.26 or absolute difference ±1.2were identified and annotated with closet gene (2000 bp in eitherdirection). For visualization, alignment files were transformed intoread coverage files (20 bp bin and smooth length 50 bp) to generatebigWig files. Seqmonk and IGV were used at different steps to visualizethe data. Unless specified, command line option was used to extract datamatrix and figures were generated in R (http://www.r-project.org).K-means clustering of tag densities +/−4 kb of TSSs was determined in R(http://www.r-project.org). Table 2 lists the H3NT-cleaved genesidentified within each cluster. To study the functional significance ofall H3NT-cleaved genes as well as the independent P, CR and P+CRclusters, Applicants quarried the Wikipathway database (Pico et al.2008). A ranked p-value was computed from the fisher exact test based onthe bionomical distribution and independence for probability of any genebelonging to any enriched set. As shown in FIG. 13E, all three clustersas well as P and CR clusters (but not P+CR, p>0.9) individuallydisplayed a significant enrichment in RANKL and associatedosteoclastogenic pathways (p<0.0001).

PCR

qPCR was performed using PerfeCta® SYBR Green FastMix (QuantaBIOSCIENCES) and an iCycler IQ5 (Bio-Rad). Primers are: Nfatc1 (P:5′-GAAGTGGTAGCCCACGTGAT (SEQ ID NO: 1), 5′-TCTTGGCACCACATAAACCA (SEQ IDNO: 2); CR: 5′-GGGTCAGTGTGACCGAAGAT (SEQ ID NO: 3),5′-GGAAGTCAGAAGTGGGTGGA (SEQ ID NO: 4); mRNA: 5′-CTCGAAAGACAGCACTGGAGCAT(SEQ ID NO: 5), 5′-CGGCTGCCTTCCGTCTCATAG) (SEQ ID NO: 6), Lif (P:5′-CTCTGGCTGTCCTGGAACTC (SEQ ID NO: 7), 5′-CCAGGACCAGGTGAAACACT (SEQ IDNO: 8); CR: 5′-ATCTTGTGGCTTTGCCAACT (SEQ ID NO: 9),5′-AGTCCTTGCCTGTCTTTCCA (SEQ ID NO: 10); mRNA: 5′-AGAAGGTCCTGAACCCCACT(SEQ ID NO: 11), 5′-AGAAGGTCCTGAACCCCACT-3′ (SEQ ID NO: 12)) and Xpr1(P: 5′-AGGACCTTCGGAAGAGCAGT (SEQ ID NO: 13), 5′-CAGCAAGCAGCTCATAACCA(SEQ ID NO: 14); CR: 5′-GGTGGGTTCCACTGAAAGAA (SEQ ID NO: 15),5′-GGTTCCTCTGACCAAAAGCA (SEQ ID NO: 16); mRNA: 5′-AGGAGCGTGTCCAACATAGG(SEQ ID NO: 17), 5′-CCACGAGATGTTTCCAGGAT (SEQ ID NO: 18)). Specificityof amplification was determined by melting curve analysis and allsamples were run in triplicate with results averaged.

Cell transduction, inhibition, chromatin extraction, Western blotanalysis, antibodies, chromatography and PCR primers are detailedherein.

Cell Culture

Primary mouse OCP cells were derived, maintained and differentiated aspreviously described (An et al. 2014). Briefly, bone marrow (BM) cellswere harvested by flushing femurs and tibias from 6- to 8-week-oldC57BL/6 mice. Cells were cultured in a-minimum essential medium (α-MEM)supplemented with M-CSF (5 ng/ml) and 10% FBS for 16 hours. Non-adherentcells were harvested and cultured with M-CSF (30 ng/ml) for three days.Floating cells were removed. Adherent cells were used to generateosteoclasts. Adherent cells were cultured in the presence of M-CSF (30ng/ml) and RANKL (50 ng/ml). On day 3, the cells were fixed and stainedfor tartrate-resistant acid phosphatase (TRAP) using a TRAP kit (Sigma).

Recombinant Proteins and H3 Cleavage Assays

His-tagged proteins were generated in Rosetta 2 (DE3) pLysS E. coli(Novagen) and purified as previously described (Kim et al. 2008).Recombinant and native histone octamers and nucleosome arrays wereprepared as previously described (Kim et al. 2012). Cell extracts orrecombinant proteins were incubated with histone octamer (1 μg) ornucleosomes (2 μg)+/−protease inhibitors and H3NT cleavage wasdetermined by Western blot analysis. H3 peptides (aa10-35) weresynthesized (EZBiolab) and incubated with rMMP-9 at increasingconcentrations. Peptide hydrolysis was measured using a Plate Chameleonspectrofluorometer (Hidex) and kinetic parameters were determined byMichaelis-Menten analysis.

ChIPac-Seq

Cells were fixed with methylene blue (Sigma). Crosslinking was confirmedby SDS-chloroform-isoamyl alcohol (SDS-CIA) of extracted chromatin priorto acetylation with acetic anhydride. Acetylated chromatin wasimmunoprecipitated with an H3K14ac-specific antibody (Active Motif) oran H3 C-terminal (H3CT) antibody (Abcam). Libraries were constructed,sequenced and aligned to the mm9 reference genome (Li et al. 2008). Eachread was extended in the sequencing orientation to a total of 200 basesto infer nucleosome coverage at each genomic position. Signal densitywas calculated in sliding 1 kb windows and aligned reads were consideredto be within a window of the midpoint of its estimated fragment.Mid-points in each window were counted and empirical distributions ofwindow counts were created. Genomic bins containing statisticallysignificant regions were identified based on background distribution ofrandomized reads specific for each sample (Kim et al. 2013b). Thengs.plot was used to calculate the average coverage of TSSs andcomposite plots were generated by averaging reads in 200 bp windows(Shen et al. 2014). Peaks were annotated with non-overlapping genes fromEnsembl. K-means clustering of tag densities +/−4 kb of TSSs wasdetermined in R (http://www.r-project.org).

RNA-Seq

Libraries were generated from total RNA for sequencing. High qualityreads were aligned to mm9 using TopHat in conjunction with gene modelfrom Ensembl release 61 (Kim et al. 2013b). Data was quantitated bycounting number of RPKM (Mortazavi et al. 2008). The values wereadjusted globally by matching count distributions at the 75th percentileand then adjusting counts to a uniform distribution between samples.Differential expression was estimated by selecting transcripts thatdisplayed significant changes (p<0.05) after Benjamini and Hochbergcorrection using null model constructed from 1% of transcripts showingthe closet average level of observation to estimate experimental noise.The gene list was ranked using fold change criteria. GSEA and leadingedge analysis was performed on the ranked list using gene sets from theC2 collection of the GSEA Molecular Signatures Database v3.0 and severalgene sets associated with bone remodeling.

Treating a Subject with Abnormal Bone Mineral Density

The levels or function of MMP-9 can be modulated to treat a subject inneed thereof. A subject in need of MMP-9 modulation includes a patientwith low bone mineral density (BMD) or high BMD, and/or a subject with abone related disease or condition selected from osteoporosis, bonecancer, cancer that has metastasized to the bone, cancer-inducedosteolysis, sepsis, rheumatoid arthritis, periodontitis, osteopetrosis,pycondysostosis, osteopoikilosis, meloreostosis, sclerosteosis, vanBuchem's disease, LRP5 high bone mass, LRP4 high bone mass,craniometaphyseal dysplasia, Camurati-Engelmann disease, Ghosalsyndrome, bone cancer, cancer metastasized to the bone, fluorosis, renalosteodystrophy, acromegaly, hepatitis C-associated osteosclerosis,myelofibrosis, mastocytosis, osseous tuberous sclerosis, Paget'sdisease, and SAPHO syndrome. Patients with the above-listed diseases orconditions require either activation or suppression ofosteoclastogenesis. For example, in a subject with low BMD, it isdesirable to inhibit osteoclastogenesis to prevent loss of bone tissue.In a subject with high BMD, it is desirable to activateosteoclastogenesis to promote bone resorbtion.

Measurement of BMD is well known in the art. A common BMD test is acentral dual-energy x-ray absorptiometry, or central DXA test. NormalBMD values vary based on age, gender, and other environmental factorsbut the World Health Organization generally defines normal as within onestandard deviation (SD) of the young adult mean. Low bone mass isindicated by BMD values between 1 and 2.5 SD below the young adult mean.Osteoporosis is indicated by BMD more than 2.5 SD below the young adultmean. Success of treatment can be measured by restoring the subject'sBMD to normal values or improving the subject's BMD closer to normalvalues.

To suppress osteoclastogenesis, an effective amount of an agent isadministered to a subject to deplete or inhibit the function of MMP-9.MMP-9 can be directly depleted and/or inhibited by administration of aneffective amount of an MMP-9 inhibitor, knockdown with interfering RNAdirected to MMP-9 RNA and/or knockdown with shRNA delivered bycontacting the cell, tissue, or subject with an effective amount of theshRNA, transfecting the cell, tissue, or subject with a polynucleotideexpression vector that encodes the shRNA, or administering an effectiveamount of cells expressing the shRNA such as mesenchymal stem cells.MMP-9 function may also be inhibited by treatment with a broadlyreactive metalloprotease inhibitor or by inhibition of enzymes thatacetylate MMP-9's target cleavage site such as CBP/p300. Once MMP-9function is attenuated, the osteoclastogenesis pathway in the cell,tissue, or subject will not be activated.

To activate osteoclastogenesis, MMP-9 function is activated and/or itsexpression levels are increased in a cell, tissue, or subject. MMP-9function specific to osteoclastogenesis can be increased by promotingadditional import of MMP-9 to the nucleus by adding nuclear localizationsignals to the enzyme. MMP-9 activity in the nucleus may also beincreased by increasing the levels of acetylation at the MMP-9 targetsite and/or by over-expression of MMP-9. Subjects with abnormally highbone mineral density can be treated by administration of an effectiveamount of nuclear MMP-9 and/or administration of an effective amount ofgenetically engineered stem cells or osteoclast precursor cells thatectopically express MMP-9. Increased MMP-9 activity will then stimulateosteoclastogenesis which results in bone resorbtion.

Accession Numbers

Sequencing data sets were deposited at NCBI GEO (GSE72846 and GSE72957).

The contents of the articles, patents, and patent applications, and allother documents and electronically available information mentioned orcited herein, are hereby incorporated by reference in their entirety tothe same extent as if each individual publication was specifically andindividually indicated to be incorporated by reference.

Applicants reserve the right to physically incorporate into thisapplication any and all materials and information from any sucharticles, patents, patent applications, or other physical and electronicdocuments.

The disclosures illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising”, “including,”containing”, etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claims. Thus, itshould be understood that although the present disclosure has beenspecifically disclosed by preferred embodiments and optional features,modification and variation of the disclosures embodied therein hereindisclosed may be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis disclosure.

The disclosure has been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thegeneric disclosure also form part of the disclosure. This includes thegeneric description of the disclosure with a proviso or negativelimitation removing any subject matter from the genus, regardless ofwhether or not the excised material is specifically recited herein.Other embodiments are within the following claims. In addition, wherefeatures or aspects of the disclosure are described in terms of Markushgroups, those skilled in the art will recognize that the disclosure isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group.

SEQ ID NO. 22

MATRIX METALLOPROTEINASE-9 PREPROPROTEIN [HOMO SAPIENS]

NCBJ Reference Sequence: NP_004985.2

LOCUS NP_004985 707 aa linear PRI 15 Mar. 2015DEFINITION matrix metalloproteinase-9 preproprotein [Homo sapiens].

ACCESSION NP_004985 VERSION NP_004985.2 GI:74272287

DBSOURCE REFSEQ: accession NM_004994.2

KEYWORDS RefSeq.

SOURCE Homo sapiens (human)

ORGANISM Homo sapiens

-   -   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata;        Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates;        Haplorrhini; Catarrhini; Hominidae; Homo.

FEATURES Location/Qualifiers

source 1 . . . 707

-   -   /organism=“Homo sapiens”    -   /db_xref=“taxon:9606”    -   /chromosome=“20”    -   /map=“20q13.12”

Protein 1 . . . 707

-   -   /product=“matrix metalloproteinase-9 preproprotein”    -   /EC_number=“3.4.24.35”    -   /note=“type V collagenase; matrix metalloproteinase 9        (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase);        macrophage gelatinase; matrix metallopeptidase 9 (gelatinase B,        92 kDa gelatinase, 92 kDa type IV collagenase)”

sig peptide 1 . . . 19

-   -   /inference=“COORDINATES: ab initio prediction:SignalP:4.0”    -   /calculated_mol_wt=2106

proprotein 20 . . . 707

-   -   /product=“matrix metalloproteinase-9 proprotein”    -   /calculated_mol_wt=76371

Site 59 . . . 60

-   -   /site_type=“cleavage”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“Cleavage, by MMP3; propagated from UniProtKB/Swiss-Prot        (P14780.3)”

Region 97 . . . 104

-   -   /region_name=“Cysteine switch. {ECO:0000250}”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“propagated from UniProtKB/Swiss-Prot (P14780.3)”

Site 106 . . . 107

-   -   /site_type=“cleavage”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“Cleavage, by MMP3; propagated from UniProtKB/Swiss-Prot        (P14780.3)”

mat peptide 107 . . . 707

-   -   /product=“82 kDa matrix metalloproteinase-9”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“propagated from UniProtKB/Swiss-Prot (P14780.3)”    -   /calculated_mol_wt=66610

Region 115 . . . 444

-   -   /region_name=“Peptidase_M10”    -   /note=“Matrixin; pfam00413”    -   /db_xref=“CDD:249842”

Region 115 . . . 444

-   -   /region_name=“ZnMc_MMP”    -   /note=“Zinc-dependent metalloprotease, matrix metalloproteinase        (MMP) sub-family. MMPs are responsible for a great deal of        pericellular proteolysis of extracellular matrix and cell        surface molecules, playing crucial roles in morphogenesis, cell        fate . . . ; cd04278”    -   /db_xref=“CDD:239805”

Site order(167, 179, 186 . . . 192, 201, 401 . . . 402, 411, 421 . . .423)

-   -   /site_type=“other”    -   /note=“TIMP-binding surface”    -   /db_xref=“CDD:239805”

Region 224 . . . 271

-   -   /region_name=“FN2”    -   /note=“Fibronectin Type II domain: FN2 is one of three types of        internal repeats which combine to form larger domains within        fibronectin. Fibronectin, a plasma protein that binds cell        surfaces and various compounds including collagen, fibrin,        heparin, DNA, and . . . ; cd00062”    -   /db_xref=“CDD:238019”

Site order(234,236,241,255,262,268,270)

-   -   /site_type=“other”    -   /note=“putative gelatin-binding site”    -   /db_xref=“CDD:238019”

Region 282 . . . 329

-   -   /region_name=“FN2”    -   /note=“Fibronectin Type II domain: FN2 is one of three types of        internal repeats which combine to form larger domains within        fibronectin. Fibronectin, a plasma protein that binds cell        surfaces and various compounds including collagen, fibrin,        heparin, DNA, and . . . ; cd00062”    -   /db_xref=“CDD:238019”

Site order(292,294,299,313,320,326,328)

-   -   /site_type=“other”    -   /note=“putative gelatin-binding site”    -   /db_xref=“CDD:238019”

Region 341 . . . 388

-   -   /region_name=“FN2”    -   /note=“Fibronectin Type II domain: FN2 is one of three types of        internal repeats which combine to form larger domains within        fibronectin. Fibronectin, a plasma protein that binds cell        surfaces and various compounds including collagen, fibrin,        heparin, DNA, and . . . ; cd00062”    -   /db_xref=“CDD:238019”

Site order(351,353,358,372,379,385,387)

-   -   /site_type=“other”    -   /note=“putative gelatin-binding site”    -   /db_xref=“CDD:238019”

Site order(401 . . . 402,405,411)

-   -   /site_type=“active”    -   /db_xref=“CDD:239805”

Region 472 . . . 506

-   -   /region_name=“PT”    -   /note=“PT repeat; pfam04886”    -   /db_xref=“CDD:113652”

Region 514 . . . 704

-   -   /region_name=“HX”    -   /note=“Hemopexin-like repeats; Hemopexin is a heme-binding        protein that transports heme to the liver. Hemopexin-like        repeats occur in vitronectin and some matrix metalloproteinases        family (matrixins). The HX repeats of some matrixins bind tissue        inhibitor of . . . ; cd00094”    -   /db_xref=“CDD:238046”

Region 518 . . . 563

-   -   /region_name=“Hemopexin 1”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“propagated from UniProtKB/Swiss-Prot (P14780.3)”

Site order(522,524,568,570,614,616,662,664)

-   -   /site_type=“metal-binding”    -   /note=“Metal binding sites [ion binding]”    -   /db_xref=“CDD:238046”

Region 564 . . . 608

-   -   /region_name=“Hemopexin 2”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“propagated from UniProtKB/Swiss-Prot (P14780.3)”

Region 610 . . . 657

-   -   /region_name=“Hemopexin 3”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“propagated from UniProtKB/Swiss-Prot (P14780.3)”

Region 658 . . . 704

-   -   /region_name=“Hemopexin 4”    -   /experiment=“experimental evidence, no additional details        recorded”    -   /note=“propagated from UniProtKB/Swiss-Prot (P14780.3)”

CDS 1 . . . 707

-   -   /gene=“MMP9”    -   /gene_synonym=“CLG4B; GELB; MANDP2; MMP-9”    -   /coded_by=“NM_004994.2:20 . . . 2143”    -   /db_xref=“CCDS:CCDS13390.1”    -   /db_xref=“GeneID:4318”    -   /db_xref=“HGNC:HGNC:7176”    -   /db_xref=“MIM:120361”

ORIGIN (SEQ ID. NO: 22)   1mslwqplvlv llvlgccfaa prqrqstlvl fpgdlrtnlt drqlaeeyly rygytrvaem  61rgeskslgpa llllqkqlsl petgeldsat lkamrtprcg vpdlgrfqtf egdlkwhhhn 121itywiqnyse dlpravidda farafalwsa vtpltftrvy srdadiviqf gvaehgdgyp 181fdgkdgllah afppgpgiqg dahfdddelw slgkgvvvpt rfgnadgaac hfpfifegrs 241ysacttdgrs dglpwcstta nydtddrfgf cpserlytqd gnadgkpcqf pfifqgqsys 301acttdgrsdg yrwcattany drdklfgfcp tradstvmgg nsagelcvfp ftflgkeyst 361ctsegrgdgr lwcattsnfd sdkkwgfcpd qgyslflvaa hefghalgld hssvpealmy 421pmyrftegpp lhkddvngir hlygprpepe prppttttpq ptapptvcpt gpptvhpser 481ptagptgpps agptgpptag pstattvpls pvddacnvni fdaiaeignq lylfkdgkyw 541rfsegrgsrp qgpfliadkw palprkldsv feerlskklf ffsgrqvwvy tgasvlgprr 601ldklglgadv aqvtgalrsg rgkmllfsgr rlwrfdvkaq mvdprsasev drmfpgvpld 661thdvfqyrek ayfcqdrfyw rvssrselnq vdqvgyvtyd ilqcped.

REFERENCES

-   1. Allan J, Harborne N, Rau D C, Gould H. 1982. Participation of    core histone “tails” in the stabilization of the chromatin solenoid.    The Journal of cell biology 93: 285-297.-   2. Allis C D, Bowen J K, Abraham G N, Glover C V, Gorovsky    M A. 1980. Proteolytic processing of histone H3 in chromatin: a    physiologically regulated event in Tetrahymena micronuclei. Cell 20:    55-64.-   3. An D, Kim K, Lu W. 2014. Defective entry into mitosis 1 (Dim1)    negatively regulates osteoclastogenesis by inhibiting the expression    of nuclear factor of activated T-cells, cytoplasmic,    calcineurin-dependent 1 (NFATc1). J Biol Chem 289: 24366-24373.-   4. Andresen K, Jimenez-Useche I, Howell S C, Yuan C, Qiu X. 2013.    Solution scattering and FRET studies on nucleosomes reveal DNA    unwrapping effects of H3 and H4 tail removal. PLoS One 8: e78587.-   5. Asp P, Blum R, Vethantham V, Parisi F, Micsinai M, Cheng J,    Bowman C, Kluger Y, Dynlacht B D. 2011. Genome-wide remodeling of    the epigenetic landscape during myogenic differentiation. Proc Natl    Acad Sci USA 108: E149-158.-   6. Azad G K, Tomar R S. 2014. Proteolytic clipping of histone tails:    the emerging role of histone proteases in regulation of various    biological processes. Molecular biology reports 41: 2717-2730.-   7. Bannister A J, Zegerman P, Partridge J F, Miska E A, Thomas J O,    Allshire R C, Kouzarides T. 2001. Selective recognition of    methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature    410: 120-124.-   8. Black J C, Van Rechem C, Whetstine J R. 2012. Histone lysine    methylation dynamics: establishment, regulation, and biological    impact. Mol Cell 48: 491-507.-   9. Bortvin A, Winston F. 1996. Evidence that Spt6p controls    chromatin structure by a direct interaction with histones. Science    272: 1473-1476.-   10. Bozec A, Bakiri L, Hoebertz A, Eferl R, Schilling A F,    Komnenovic V, Scheuch H, Priemel M, Stewart C L, Amling M et    al. 2008. Osteoclast size is controlled by Fra-2 through    LIF/LIF-receptor signalling and hypoxia. Nature 454: 221-225.-   11. Cackowski F C, Anderson J L, Patrene K D, Choksi R J, Shapiro S    D, Windle J J, Blair H C, Roodman G D. 2010. Osteoclasts are    important for bone angiogenesis. Blood 115: 140-149.-   12. Colnot C, Thompson Z, Miclau T, Werb Z, Helms J A. 2003. Altered    fracture repair in the absence of MMP9. Development 130: 4123-4133.-   13. Dhaenens M, Glibert P, Meert P, Vossaert L, Deforce D. 2015.    Histone proteolysis: a proposal for categorization into ‘clipping’    and ‘degradation’. BioEssays: news and reviews in molecular,    cellular and developmental biology 37: 70-79.-   14. Duarte L F, Young A R, Wang Z, Wu H A, Panda T, Kou Y, Kapoor A,    Hasson D, Mills N R, Ma'ayan A et al. 2014. Histone H3.3 and its    proteolytically processed form drive a cellular senescence    programme. Nature communications 5: 5210.-   15. Duncan E M, Muratore-Schroeder T L, Cook R G, Garcia B A,    Shabanowitz J, Hunt D F, Allis C D. 2008. Cathepsin L    proteolytically processes histone H3 during mouse embryonic stem    cell differentiation. Cell 135: 284-294.-   16. Franco G C, Kajiya M, Nakanishi T, Ohta K, Rosalen P L, Groppo F    C, Ernst C W, Boyesen J L, Bartlett J D, Stashenko P et al. 2011.    Inhibition of matrix metalloproteinase-9 activity by doxycycline    ameliorates RANK ligand-induced osteoclast differentiation in vitro    and in vivo. Experimental cell research 317: 1454-1464.-   17. Henry R A, Kuo Y M, Andrews A J. 2013. Differences in    specificity and selectivity between CBP and p300 acetylation of    histone H3 and H3/H4. Biochemistry 52: 5746-5759.-   18. Khalkhali-Ellis Z, Goossens W, Margaryan N V, Hendrix M J. 2014.    Cleavage of Histone 3 by Cathepsin D in the involuting mammary    gland. PLoS One 9: e103230.-   19. Kim K, Choi J, Heo K, Kim H, Levens D, Kohno K, Johnson E M,    Brock H W, An W. 2008. Isolation and characterization of a novel    H1.2 complex that acts as a repressor of p53-mediated transcription.    J Biol Chem 283: 9113-9126.-   20. Kim K, Heo K, Choi J, Jackson S, Kim H, Xiong Y, An W. 2012.    Vpr-binding protein antagonizes p53-mediated transcription via    direct interaction with H3 tail. Mol Cell Biol 32: 783-796.-   21. Kim K, Kim J M, Kim J S, Choi J, Lee Y S, Neamati N, Song J S,    Heo K, An W. 2013a. VprBP has intrinsic kinase activity targeting    histone H2A and represses gene transcription. Mol Cell 52: 459-467.-   22. Kim K, Punj V, Choi J, Heo K, Kim J M, Laird P W, An W. 2013b.    Gene dysregulation by histone variant H2A.Z in bladder cancer.    Epigenetics & chromatin 6: 34.-   23. Lalwani R, Maiti S, Mukherji S. 1990. Visible light induced    DNA-protein crosslinking in DNA-histone complex and sarcoma-180    chromatin in the presence of methylene blue. Journal of    photochemistry and photobiology B, Biology 7: 57-73.-   24. Li H, Ruan J, Durbin R. 2008. Mapping short DNA sequencing reads    and calling variants using mapping quality scores. Genome research    18: 1851-1858.-   25. Luger K, Dechassa M L, Tremethick D J. 2012. New insights into    nucleosome and chromatin structure: an ordered state or a disordered    affair? Nature reviews Molecular cell biology 13: 436-447.-   26. Mannello F, Medda V. 2012. Nuclear localization of matrix    metalloproteinases. Progress in histochemistry and cytochemistry 47:    27-58.-   27. Metz B, Kersten G F, Hoogerhout P, Brugghe H F, Timmermans H A,    de Jong A, Meiring H, ten Hove J, Hennink W E, Crommelin D J et    al. 2004. Identification of formaldehyde-induced modifications in    proteins: reactions with model peptides. J Biol Chem 279: 6235-6243.-   28. Mortazavi A, Williams B A, McCue K, Schaeffer L, Wold B. 2008.    Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat    Methods 5: 621-628.-   29. Nagase H, Visse R, Murphy G. 2006. Structure and function of    matrix metalloproteinases and TIMPs. Cardiovascular research 69:    562-573.-   30. Nakayasu E S, Wu S, Sydor M A, Shukla A K, Weitz K K, Moore R J,    Hixson K K, Kim J S, Petyuk V A, Monroe M E et al. 2014. A method to    determine lysine acetylation stoichiometries. International journal    of proteomics 2014: 730725.-   31. Narlikar G J, Sundaramoorthy R, Owen-Hughes T. 2013. Mechanisms    and functions of ATP-dependent chromatin-remodeling enzymes. Cell    154: 490-503.-   32. Nurse N P, Jimenez-Useche I, Smith I T, Yuan C. 2013. Clipping    of flexible tails of histones H3 and H4 affects the structure and    dynamics of the nucleosome. Biophysical journal 104: 1081-1088.-   33. Park-Min K H, Lim E, Lee M J, Park S H, Giannopoulou E, Yarilina    A, van der Meulen M, Zhao B, Smithers N, Witherington J et al. 2014.    Inhibition of osteoclastogenesis and inflammatory bone resorption by    targeting BET proteins and epigenetic regulation. Nature    communications 5: 5418.-   34. Pauli A, van Bemmel J G, Oliveira R A, Itoh T, Shirahige K, van    Steensel B, Nasmyth K. 2010. A direct role for cohesin in gene    regulation and ecdysone response in Drosophila salivary glands. Curr    Biol 20: 1787-1798.-   35. Phillips D M, Johns E W. 1959. A study of the proteinase content    and the chromatography of thymus histones. The Biochemical journal    72: 538-544.-   36. Polak P, Karlic R, Koren A, Thurman R, Sandstrom R, Lawrence M    S, Reynolds A, Rynes E, Vlahovicek K, Stamatoyannopoulos J A et    al. 2015. Cell-of-origin chromatin organization shapes the    mutational landscape of cancer. Nature 518: 360-364.-   37. Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilcnky    M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J et    al. 2015. Integrative analysis of 111 reference human epigenomes.    Nature 518: 317-330.-   38. Santos-Rosa H, Kirmizis A, Nelson C, Bartke T, Saksouk N, Cote    J, Kouzarides T. 2009. Histone H3 tail clipping regulates gene    expression. Nature structural & molecular biology 16: 17-22.-   39. Seto E, Yoshida M. 2014. Erasers of histone acetylation: the    histone deacetylase enzymes. Cold Spring Harbor perspectives in    biology 6: a018713.-   40. Sharma P, Patntirapong S, Hann S, Hauschka P V. 2010. RANKL-RANK    signaling regulates expression of xenotropic and polytropic virus    receptor (XPR1) in osteoclasts. Biochemical and biophysical research    communications 399: 129-132.-   41. Shen L, Shao N, Liu X, Nestler E. 2014. ngs.plot: Quick mining    and visualization of next-generation sequencing data by integrating    genomic databases. BMC genomics 15: 284.-   42. Shogren-Knaak M, Ishii H, Sun J M, Pazin M J, Davie J R,    Peterson C L. 2006. Histone H4-K16 acetylation controls chromatin    structure and protein interactions. Science 311: 844-847.-   43. Shogren-Knaak M A, Peterson C L. 2004. Creating designer    histones by native chemical ligation. Methods in enzymology 375:    62-76.-   44. Song J, Tan H, Perry A J, Akutsu T, Webb G I, Whisstock J C,    Pike R N. 2012. PROSPER: an integrated feature-based tool for    predicting protease substrate cleavage sites. PLoS One 7: e50300.-   45. Strahl B D, Allis C D. 2000. The language of covalent histone    modifications. Nature 403: 41-45.-   46. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H,    Saiura A, Isobe M, Yokochi T, Inoue J et al. 2002. Induction and    activation of the transcription factor NFATc1 (NFAT2) integrate    RANKL signaling in terminal differentiation of osteoclasts.    Developmental cell 3: 889-901.-   47. Tuite E M, Kelly J M. 1993. Photochemical interactions of    methylene blue and analogues with DNA and other biological    substrates. Journal of photochemistry and photobiology B, Biology    21: 103-124.-   48. Vossaert L, Meert P, Scheerlinck E, Glibert P, Van Roy N,    Heindryckx B, De Sutter P, Dhaenens M, Deforce D. 2014.    Identification of histone H3 clipping activity in human embryonic    stem cells. Stem cell research 13: 123-134.-   49. Vu T H, Shipley J M, Bergers G, Berger J E, Helms J A, Hanahan    D, Shapiro S D, Senior R M, Werb Z. 1998. MMP-9/gelatinase B is a    key regulator of growth plate angiogenesis and apoptosis of    hypertrophic chondrocytes. Cell 93: 411-422.-   50. Xue Y, Vashisht A A, Tan Y, Su T, Wohlschlegel J A. 2014. PRB1    is required for clipping of the histone H3 N terminal tail in    Saccharomyces cerevisiae. PLoS One 9: e90496.-   51. Zentner G E, Henikoff S. 2013. Regulation of nucleosome dynamics    by histone modifications. Nature structural & molecular biology 20:    259-266.-   52. Bailey T, Krajewski P, Ladunga I, Lefebvre C, Li Q, Liu T,    Madrigal P, Taslim C, Zhang J. 2013. Practical guidelines for the    comprehensive analysis of ChIP-seq data. PLoS computational biology    9: e1003326.-   53. DeLuca D S, Levin J Z, Sivachenko A, Fennell T, Nazaire M D,    Williams C, Reich M, Winckler W, Getz G. 2012. RNA-SeQC: RNA-seq    metrics for quality control and process optimization. Bioinformatics    28: 1530-1532.-   54. Diaz A, Park K, Lim D A, Song J S. 2012. Normalization, bias    correction, and peak calling for ChIP-seq. Statistical applications    in genetics and molecular biology 11: Article 9.-   55. Garcia-Alcalde F, Okonechnikov K, Carbonell J, Cruz L M, Gotz S,    Tarazona S, Dopazo J, Meyer T F, Conesa A. 2012. Qualimap:    evaluating next-generation sequencing alignment data. Bioinformatics    28: 2678-2679.-   56. Graw S, Meier R, Minn K, Bloomer C, Godwin A K, Fridley B, Vlad    A, Beyerlein P, Chien J. 2015. Robust gene expression and mutation    analyses of RNA-sequencing of formalin-fixed diagnostic tumor    samples. Scientific reports 5: 12335.-   57. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S L.    2013a. TopHat2: accurate alignment of transcriptomes in the presence    of insertions, deletions and gene fusions. Genome biology 14: R36.-   58. Kim J M, Kim K, Schmidt T, Punj V, Tucker H, Rice J C, Ulmer T    S, An W. 2015. Cooperation between SMYD3 and PC4 drives a distinct    transcriptional program in cancer cells. Nucleic acids research 43:    8868-8883.-   59. Kim K, Choi J, Heo K, Kim H, Levens D, Kohno K, Johnson E M,    Brock H W, An W. 2008. Isolation and characterization of a novel    H1.2 complex that acts as a repressor of p53-mediated transcription.    J Biol Chem 283: 9113-9126.-   60. Kim K, Heo K, Choi J, Jackson S, Kim H, Xiong Y, An W. 2012.    Vpr-binding protein antagonizes p53-mediated transcription via    direct interaction with H3 tail. Mol Cell Biol 32: 783-796.-   61. Kim K, Lee B, Kim J, Choi J, Kim J M, Xiong Y, Roeder R G, An W.    2013b. Linker Histone H1.2 cooperates with Cul4A and PAF1 to drive    H4K31 ubiquitylation-mediated transactivation. Cell reports 5:    1690-1703.-   62. Kim K, Punj V, Choi J, Heo K, Kim J M, Laird P W, An W. 2013c.    Gene dysregulation by histone variant H2A.Z in bladder cancer.    Epigenetics & chromatin 6: 34.-   63. Kramer J M, Kochinke K, Oortveld M A, Marks H, Kramer D, de Jong    E K, Asztalos Z, Westwood J T, Stunnenberg H G, Sokolowski M B et    al. 2011. Epigenetic regulation of learning and memory by Drosophila    EHMT/G9a. PLoS biology 9: e1000569.-   64. Landt S G, Marinov G K, Kundaje A, Kheradpour P, Pauli F,    Batzoglou S, Bernstein B E, Bickel P, Brown J B, Cayting P et    al. 2012. ChIP-seq guidelines and practices of the ENCODE and    modENCODE consortia. Genome research 22: 1813-1831.-   65. Lassmann T, Hayashizaki Y, Daub C O. 2011. SAMStat: monitoring    biases in next generation sequencing data. Bioinformatics 27:    130-131.-   66. Li H, Ruan J, Durbin R. 2008. Mapping short DNA sequencing reads    and calling variants using mapping quality scores. Genome research    18: 1851-1858.-   67. Mortazavi A, Williams B A, McCue K, Schaeffer L, Wold B. 2008.    Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat    Methods 5: 621-628.-   68. Pico A R, Kelder T, van Iersel M P, Hanspers K, Conklin B R,    Evclo C. 2008. WikiPathways: pathway editing for the people. PLoS    biology 6: e184.-   69. Ring A, Mineyev N, Zhu W, Park E, Lomas C, Punj V, Yu M, Barrak    D, Forte V, Porras T et al. 2015. EpCAM based capture detects and    recovers circulating tumor cells from all subtypes of breast cancer    except claudin-low. Oncotarget.-   70. Shen L, Shao N, Liu X, Nestler E. 2014. ngs.plot: Quick mining    and visualization of next-generation sequencing data by integrating    genomic databases. BMC genomics 15: 284.-   71. Ye T, Krebs A R, Choukrallah M A, Keime C, Plewniak F, Davidson    I, Tora L. 2011. seqMINER: an integrated ChIP-seq data    interpretation platform. Nucleic acids research 39: e35.

TABLE 1 Differential MMP9sh vs expressin MMP-9sh 3d NCsh 3d NCsh (log2Gene p-value ID Description (log2 ratio) RANKL RNAKL ratio) Tspan105.83763E−08 ENSMUSG00000039691 tetraspanin −7.4485833 −5.39562462.0529587 −7.4485833 10 Gm13057 3.0793E−06 ENSMUSG00000078514 predicted−7.171078 −5.5476274 1.6234506 −7.171078 gene 13057 Gm13040 7.74498E−05ENSMUSG00000070616 predicted −7.171078 −5.5476274 1.6234506 −7.171078gene 13040 Rhov 3.82912E−06 ENSMUSG00000034226 ras homolog −6.6498415−5.3956246 1.2542169 −6.6498415 gene family, member V Itgb3 0.000171214ENSMUSG00000020689 integrin beta 3 −6.5923559 −1.0736963 5.5186596−6.5923559 Matk 0.000250093 ENSMUSG00000004933 megakaryocyte- −6.4593418−2.3956244 4.0637174 −6.4593418 associated tyrosine kinase Ctsk0.000214337 ENSMUSG00000028111 cathepsin K −6.446837 5.423756 11.870593−6.446837 Cldn11 7.28667E−05 ENSMUSG00000037625 claudin 11 −5.5788259−0.2256994 5.3531265 −5.5788259 Bai1 0.000475161 ENSMUSG00000034730brain-specific −5.4648093 −5.5476274 −0.0828181 −5.4648093 angiogenesisinhibitor 1 Htr1b 6.37744E−05 ENSMUSG00000049511 5- −5.4282835−2.8106618 2.6176217 −5.4282835 hydroxytryptamine (serotonin) receptor1B D430036J16Rik 0.000806317 ENSMUSG00000085832 RIKEN cDNA −5.2213831−2.8106618 2.4107213 −5.2213831 D430036J16 gene Lif 0.00083463ENSMUSG00000034394 leukemia −5.2032929 −0.6407369 4.562556 −5.2032929inhibitory factor Gm1123 0.013656123 ENSMUSG00000044860 predicted−5.1941621 −5.3956246 −0.2014625 −5.1941621 gene 1123 Gm106960.015074948 ENSMUSG00000074424 predicted −5.1710781 −5.5476274−0.3765493 −5.1710781 gene 10696 Mmp9 5.50763E−09 ENSMUSG00000017737matrix −5.1696789 1.9531038 7.1227827 −5.1696789 metallopeptidase 9Gm15448 0.002977603 ENSMUSG00000074419 predicted −5.1237725 −3.81066181.3131107 −5.1237725 gene 15448 Mapk4 0.016108619 ENSMUSG00000024558mitogen- −5.1237724 −5.5476274 −0.423855 −5.1237724 activated proteinkinase 4 Zscan4c 0.017287914 ENSMUSG00000054272 zinc finger −5.1092732−5.3956246 −0.2863514 −5.1092732 and SCAN domain containing 4C Gm131190.000839543 ENSMUSG00000070619 predicted −5.0748629 −5.5476274−0.4727645 −5.0748629 gene 13119 Atp2b3 0.017654449 ENSMUSG00000031376ATPase, Ca++ −5.0748629 −5.5476274 −0.4727645 −5.0748629 transporting,plasma membrane 3 Prss46 0.005045636 ENSMUSG00000049719 protease,−5.0497718 −2.8106618 2.23911 −5.0497718 serine, 46 Ccr3 0.000166384ENSMUSG00000035448 chemokine −5.0467314 −2.0736964 2.973035 −5.0467314(C-C motif) receptor 3 Dgki 0.000827937 ENSMUSG00000038665diacylglycerol −5.0345051 −2.8106618 2.2238433 −5.0345051 kinase, iotaGm7971 0.01710386 ENSMUSG00000079422 predicted −5.0242368 −5.5476274−0.5233907 −5.0242368 gene 7971 Gm16429 0.01720231 ENSMUSG00000072823predicted −5.0242368 −5.5476274 −0.5233907 −5.0242368 gene 16429 Opcml0.014594807 ENSMUSG00000062257 opioid −5.0190754 −4.3956246 0.62345076−5.0190754 binding protein/cell adhesion molecule-like Zscan4d2.03004E−05 ENSMUSG00000090714 zinc finger −5.0190753 −5.3956246−0.3765493 −5.0190753 and SCAN domain containing 4D Mtus1 0.014655925ENSMUSG00000045636 mitochondrial −5.0190753 −5.3956246 −0.3765493−5.0190753 tumor suppressor 1 Fam198b 1.55975E−08 ENSMUSG00000027955family with −5.003479 1.54689 6.550369 −5.003479 sequence similarity198, member B Chst1 0.015000206 ENSMUSG00000027221 carbohydrate−4.9956165 −4.3956246 0.59999186 −4.9956165 (keratan sulfate Gal-6)sulfotransferase 1 Calml4 0.001680683 ENSMUSG00000032246 calmodulin-−4.977103 −2.2256994 2.7514036 −4.977103 like 4 H1foo 0.000716847ENSMUSG00000042279 H1 histone −4.9717696 −5.3956246 −0.423855 −4.9717696family, member O, oocyte- specific Gm10424 0.014855926ENSMUSG00000072817 predicted −4.9717696 −5.3956246 −0.423855 −4.9717696gene 10424 Ttll11 0.015697744 ENSMUSG00000026885 tubulin −4.9717696−5.3956246 −0.423855 −4.9717696 tyrosine ligase-like family, member 11Ppef2 0.015779987 ENSMUSG00000029410 protein −4.9717696 −5.3956246−0.423855 −4.9717696 phosphatase, EF hand calcium- binding domain 2D930048N14Rik 0.015629802 ENSMUSG00000052563 RIKEN cDNA −4.9717696−4.3956246 0.576145 −4.9717696 D930048N14 gene Slc4a3 0.01688572ENSMUSG00000006576 solute carrier −4.9717693 −5.5476274 −0.5758581−4.9717693 family 4 (anion exchanger), member 3 BC061212 0.017009392ENSMUSG00000072822 cDNA −4.9717693 −5.5476274 −0.5758581 −4.9717693sequence BC061212 Ccr1 1.08715E−10 ENSMUSG00000025804 chemokine−4.9647516 1.9081564 6.872908 −4.9647516 (C-C motif) receptor 1 Rtkn29.62021E−10 ENSMUSG00000037846 rhotekin 2 −4.9173215 −5.5476274−0.6303059 −4.9173215 Plxna4 0.017766215 ENSMUSG00000029765 plexin A4−4.9173215 −5.5476274 −0.6303059 −4.9173215 Mpzl3 0.000349792ENSMUSG00000070305 myelin −4.8696551 −1.0736963 3.7959588 −4.8696551protein zero- like 3 C77080 4.56735E−08 ENSMUSG00000050390 expressed−4.8508598 2.1512702 7.00213 −4.8508598 sequence C77080 Ano7 0.005485625ENSMUSG00000034107 anoctamin 7 −4.8349529 −2.5882695 2.2466834−4.8349529 Ckb 3.7182E−09 ENSMUSG00000001270 creatine −4.83180954.1141505 8.94596 −4.8318095 kinase, brain Sorbs2 0.005497429ENSMUSG00000031626 sorbin and −4.8273795 −2.5882695 2.23911 −4.8273795SH3 domain containing 2 Tdp0z5 0.026959086 ENSMUSG00000074427 TD and POZ−4.8018443 −5.5476274 −0.7457831 −4.8018443 domain containing 5 Gm106970.02758078 ENSMUSG00000074425 predicted −4.8018443 −5.5476274 −0.7457831−4.8018443 gene 10697 Gm5286 0.028164925 ENSMUSG00000090268 predicted−4.8018443 −5.5476274 −0.7457831 −4.8018443 gene 5286 Fam46c 0.028858004ENSMUSG00000044468 family with −4.8018443 −5.5476274 −0.7457831−4.8018443 sequence similarity 46, member C Gm6346 0.029553404ENSMUSG00000091252 predicted −4.8018443 −5.5476274 −0.7457831 −4.8018443gene 6346 Cthrc1 0.030250954 ENSMUSG00000054196 collagen −4.8018443−5.5476274 −0.7457831 −4.8018443 triple helix repeat containing 1 Gm220.003586833 ENSMUSG00000043903 predicted −4.7791244 −2.3956244 2.3835−4.7791244 gene 22 Adck3 4.30239E−06 ENSMUSG00000026489 aarF domain−4.770136 1.1279377 5.8980737 −4.770136 containing kinase 3 Tnfsf120.000393042 ENSMUSG00000090170 tumor −4.7429509 −3.0736964 1.6692545−4.7429509 necrosis factor (ligand) superfamily, member 12 Gpr1760.001955719 ENSMUSG00000040133 G protein- −4.7408358 −1.39562433.3452115 −4.7408358 coupled receptor 176 Gm7978 0.02610885ENSMUSG00000072815 predicted −4.7404438 −5.5476274 −0.8071836 −4.7404438gene 7978 Akr1c18 0.02618227 ENSMUSG00000021214 aldo-keto −4.7404438−5.5476274 −0.8071836 −4.7404438 reductase family 1, member C18 Gm152410.013268969 ENSMUSG00000087505 predicted −4.7087353 −4.39562460.31311068 −4.7087353 gene 15241 Eps8l2 0.018382147 ENSMUSG00000025504EPS8-like 2 −4.7087353 −4.3956246 0.31311068 −4.7087353 Grb10 0.00447582ENSMUSG00000020176 growth factor −4.7087351 −3.3956244 1.3131107−4.7087351 receptor bound protein 10 Akap6 9.72033E−07ENSMUSG00000061603 A kinase −4.6948978 1.0638072 5.758705 −4.6948978(PRKA) anchor protein 6 Sema7a 0.001981256 ENSMUSG00000038264 semadomain, −4.6631381 −2.2256994 2.4374387 −4.6631381 immunoglobulin domain(Ig), and GPI membrane anchor, (semaphorin) 7A Il34 0.023407776ENSMUSG00000031750 interleukin 34 −4.6498415 −5.3956246 −0.7457831−4.6498415 BC050972 2.2733E−05 ENSMUSG00000092131 cDNA −4.6498413−3.3956244 1.2542169 −4.6498413 sequence BC050972 Mras 0.001684752ENSMUSG00000032470 muscle and −4.6347343 −1.3956243 3.23911 −4.6347343microspikes RAS Arhgap31 2.67619E−08 ENSMUSG00000022799 Rho GTPase−4.6253586 1.3048154 5.930174 −4.6253586 activating protein 31 Tmcc30.012788476 ENSMUSG00000020023 transmembrane −4.619468 −4.39562460.22384338 −4.619468 and coiled coil domains 3 BC106179 0.02830728ENSMUSG00000045231 cDNA −4.6091994 −5.5476274 −0.938428 −4.6091994sequence BC106179 Gabrg2 0.028566783 ENSMUSG00000020436 gamma-−4.6091994 −5.5476274 −0.938428 −4.6091994 aminobutyric acid (GABA) Areceptor, subunit gamma 2 Siglec15 1.04139E−13 ENSMUSG00000091055 sialicacid −4.6067727 −1.3081615 3.2986112 −4.6067727 binding Ig-like lectin15 Cnn2 0.009360389 ENSMUSG00000004665 calponin 2 −4.6062522 −2.58826952.0179827 −4.6062522 Hist1h3f 0.000460235 ENSMUSG00000059309 histone−4.588441 −5.3956246 −0.8071836 −4.588441 cluster 1, H3f Msln0.014735865 ENSMUSG00000063011 mesothelin −4.588441 −4.39562460.19281639 −4.588441 B230206H07Rik 0.015672518 ENSMUSG00000086844 RIKENcDNA −4.5567322 −4.3956246 0.16110758 −4.5567322 B230206H07 gene Zscan4b0.028859515 ENSMUSG00000091643 zinc finger −4.53881 −5.5476274−1.0088174 −4.53881 and SCAN domain containing 4B Gm7682 0.029196529ENSMUSG00000074011 predicted −4.53881 −5.5476274 −1.0088174 −4.53881gene 7682 Gm6468 0.029204158 ENSMUSG00000072816 predicted −4.53881−5.5476274 −1.0088174 −4.53881 gene 6468 Gpr64 0.034004346ENSMUSG00000031298 G protein- −4.5243106 −5.3956246 −0.871314 −4.5243106coupled receptor 64 Cfhr2 0.002030646 ENSMUSG00000033898 complement−4.5111351 −1.4887338 3.0224013 −4.5111351 factor H- related 2 Myocd0.034741744 ENSMUSG00000020542 myocardin −4.4648094 −5.5476274 −1.082818−4.4648094 Gm7982 0.03488961 ENSMUSG00000072814 predicted −4.4648094−5.5476274 −1.082818 −4.4648094 gene 7982 Gm6509 0.035009217ENSMUSG00000074008 predicted −4.4648094 −5.5476274 −1.082818 −4.4648094gene 6509 Gm6502 0.03512885 ENSMUSG00000073498 predicted −4.4648094−5.5476274 −1.082818 −4.4648094 gene 6502 Gm6351 0.035928585ENSMUSG00000072821 predicted −4.4648094 −5.5476274 −1.082818 −4.4648094gene 6351 Slc18a1 1.86529E−06 ENSMUSG00000036330 solute carrier−4.4627261 0.55857193 5.021298 −4.4627261 family 18 (vesicularmonoamine), member 1 Rnf165 0.03428333 ENSMUSG00000025427 ring finger−4.4571966 −5.3956246 −0.938428 −4.4571966 protein 165 Hist1h3b0.03678912 ENSMUSG00000069267 histone −4.4571966 −5.3956246 −0.938428−4.4571966 cluster 1, H3b Nos1ap 9.11868E−06 ENSMUSG00000038473 nitricoxide −4.3043447 −5.5476274 −1.2432827 −4.3043447 synthase 1 (neuronal)adaptor protein AA986860 2.02175E−11 ENSMUSG00000042510 expressed−4.1523419 −5.3956246 −1.2432827 −4.1523419 sequence AA986860 Dmrtb14.996E−16 ENSMUSG00000028610 DMRT-like −4.1237723 −5.5476274 −1.4238551−4.1237723 family B with proline-rich C-terminal, 1 Apoa5 5.2547E−06ENSMUSG00000032079 apolipoprotein −4.0648791 −5.3956246 −1.3307455−4.0648791 A-V Sphk1 0.000200649 ENSMUSG00000061878 sphingosine−4.0097374 −2.0736964 1.936041 −4.0097374 kinase 1 Acp5 0.001185123ENSMUSG00000001348 acid −4.0066 6.829583 10.836183 −4.0066 phosphatase5, tartrate resistant Calcr 1.58852E−06 ENSMUSG00000023964 calcitonin−3.9956162 −2.3956244 1.5999918 −3.9956162 receptor E130309D14Rik0.00390218 ENSMUSG00000069814 RIKEN cDNA −3.9717695 −5.3956246−1.4238551 −3.9717695 E130309D14 gene Gm3176 0.004518255ENSMUSG00000073509 predicted −3.9228601 −4.3956246 −0.4727645 −3.9228601gene 3176 Kirrel2 0.000108978 ENSMUSG00000036915 kin of IRRE −3.9173215−5.5476274 −1.6303059 −3.9173215 like 2 (Drosophila) Gm4788 0.00511082ENSMUSG00000070594 predicted −3.9157354 −2.5882695 1.3274659 −3.9157354gene 4788 AI661453 6.6252E−10 ENSMUSG00000034382 expressed −3.8722339−5.3956246 −1.5233907 −3.8722339 sequence AI661453 Mrgpre 1.63355E−07ENSMUSG00000048965 MAS-related −3.8722339 −5.3956246 −1.5233907−3.8722339 GPR, member E Fam109a 0.003682157 ENSMUSG00000044134 familywith −3.8686511 3.3592632 7.2279143 −3.8686511 sequence similarity 109,member A Nos1 0.002229427 ENSMUSG00000029361 nitric oxide −3.8462386−3.3956244 0.45061424 −3.8462386 synthase 1, neuronal Ggt1 0.007170915ENSMUSG00000006345 gamma- −3.8197665 −4.3956246 −0.5758581 −3.8197665glutamyltransferase 1 Pramef6 0.006200188 ENSMUSG00000078512 PRAMEfamily −3.8018444 −5.5476274 −1.745783 −3.8018444 member 6 Lilra60.001267628 ENSMUSG00000030427 leukocyte −3.7810859 −2.5882695 1.1928164−3.7810859 immunoglobulin- like receptor, subfamily A (with TM domain),member 6 Gm10527 0.001781571 ENSMUSG00000073525 predicted −3.7653187−5.3956246 −1.6303059 −3.7653187 gene 10527 Gc 0.010909459ENSMUSG00000035540 group specific −3.7653187 −5.3956246 −1.6303059−3.7653187 component Cyp26b1 0.00299968 ENSMUSG00000063415 cytochrome−3.6763135 −5.5476274 −1.8713139 −3.6763135 P450, family 26, subfamilyb, polypeptide 1 Krba1 0.006188563 ENSMUSG00000042810 KRAB-A −3.6763135−5.5476274 −1.8713139 −3.6763135 domain containing 1 E230008N13Rik0.010172137 ENSMUSG00000035539 RIKEN cDNA −3.6763135 −5.5476274−1.8713139 −3.6763135 E230008N13 gene Clec4b1 5.68695E−05ENSMUSG00000030147 C-type lectin −3.6624414 −1.1476969 2.5147445−3.6624414 domain family 4, member b1 Src 0.001090707 ENSMUSG00000027646Rous sarcoma −3.651526 4.082134 7.73366 −3.651526 oncogene Lrp2bp0.013656123 ENSMUSG00000031637 Lrp2 binding −3.588441 −4.3956246−0.8071836 −3.588441 protein Plekhg5 5.50763E−09 ENSMUSG00000039713pleckstrin −3.5700286 0.18933822 3.7593668 −3.5700286 homology domaincontaining, family G (with RhoGef domain) member 5 1700019D03Rik0.002977603 ENSMUSG00000043629 RIKEN cDNA −3.53881 −5.5476274 −2.0088174−3.53881 1700019D03 gene Rnf43 0.017287914 ENSMUSG00000034177 ringfinger −3.5243107 −5.3956246 −1.8713139 −3.5243107 protein 43 Tmem2200.017654449 ENSMUSG00000050270 transmembrane −3.5243107 −5.3956246−1.8713139 −3.5243107 protein 220 Ak1 0.000166384 ENSMUSG00000026817adenylate −3.4884204 −0.186171 3.3022494 −3.4884204 kinase 1 Wipi10.005311127 ENSMUSG00000041895 WD repeat −3.461769 −1.4887338 1.9730352−3.461769 domain, phosphoinositide interacting 1 Ndrg4 0.01720231ENSMUSG00000036564 N-myc −3.4556536 3.251834 6.7074876 −3.4556536downstream regulated gene 4 Mmp14 0.01710386 ENSMUSG00000000957 matrix−3.4256262 −1.9361928 1.4894334 −3.4256262 metallopeptidase 14(membrane- inserted) Gpr56 0.014594807 ENSMUSG00000031785 G protein-−3.3868072 −5.3956246 −2.0088174 −3.3868072 coupled receptor 56 Pira50.014655925 ENSMUSG00000074417 paired-Ig-like −3.3868071 −2.07369641.3131107 −3.3868071 receptor A5 Gm13083 1.55975E−08 ENSMUSG00000066688predicted −3.3868069 −5.5476274 −2.1608205 −3.3868069 gene 13083 Smtnl20.001680683 ENSMUSG00000045667 smoothelin- −3.3868069 −5.5476274−2.1608205 −3.3868069 like 2 Hist1h1a 0.014855926 ENSMUSG00000049539histone −3.3868069 −5.5476274 −2.1608205 −3.3868069 cluster 1, H1a Abcc20.015697744 ENSMUSG00000025194 ATP-binding −3.3868069 −5.5476274−2.1608205 −3.3868069 cassette, sub- family C (CFTR/MRP), member 2 Lctl0.01688572 ENSMUSG00000032401 lactase-like −3.3352765 0.437265663.7725422 −3.3352765 Xpr1 0.017009392 ENSMUSG00000026469 xenotropic−3.3232984 5.5578446 8.881143 −3.3232984 and polytropic retrovirusreceptor 1 41701 1.08715E−10 ENSMUSG00000032656 membrane- −3.3128066−4.3956246 −1.082818 −3.3128066 associated ring finger (C3HC4) 3 Adcy30.017891841 ENSMUSG00000020654 adenylate −3.2208839 0.94422567 4.1651096−3.2208839 cyclase 3 Cfhr1 0.000349792 ENSMUSG00000057037 complement−3.2168819 −5.5476274 −2.3307455 −3.2168819 factor H- related 1 Tal20.005485625 ENSMUSG00000028417 T-cell acute −3.2168819 −5.5476274−2.3307455 −3.2168819 lymphocytic leukemia 2 Cyr61 0.005497429ENSMUSG00000028195 cysteine rich −3.2168819 −5.5476274 −2.3307455−3.2168819 protein 61 Ltbp2 0.030250954 ENSMUSG00000002020 latent−3.2023825 −2.0736964 1.1286861 −3.2023825 transforming growth factorbeta binding protein 2 Adamts14 0.026959086 ENSMUSG00000059901 adisintegrin- −3.1987347 −2.2256994 0.9730353 −3.1987347 like andmetallopeptidase (reprolysin type) with thrombospondin type 1 motif, 14Dnm1 0.02758078 ENSMUSG00000026825 dynamin 1 −3.1965845 −1.30816151.888423 −3.1965845 Pltp 0.029553404 ENSMUSG00000017754 phospholipid−3.165339 2.4747405 5.6400795 −3.165339 transfer protein Ggt61.80877E−07 ENSMUSG00000040471 gamma- −3.0648791 −5.3956246 −2.3307455−3.0648791 glutamyltransferase 6 Grin2d 0.028858004 ENSMUSG00000002771glutamate −3.0648791 −4.3956246 −1.3307455 −3.0648791 receptor,ionotropic, NMDA2D (epsilon 4) Amz1 0.001955719 ENSMUSG00000050022archaelysin −3.0345052 0.5112662 3.5457714 −3.0345052 familymetallopeptidase 1 Otx1 0.02610885 ENSMUSG00000005917 orthodenticle−3.0345052 −2.8106618 0.22384338 −3.0345052 homolog 1 (Drosophila) Lrrn40.001981256 ENSMUSG00000043110 leucine rich −3.0242366 −5.5476274−2.5233908 −3.0242366 repeat neuronal 4 Bpi 0.00447582ENSMUSG00000052922 bactericidal −3.0242366 −5.5476274 −2.5233908−3.0242366 permeablility increasing protein Kctd19 0.018382147ENSMUSG00000051648 potassium −3.0242366 −5.5476274 −2.5233908 −3.0242366channel tetramerisation domain containing 19 Lipg 0.005540829ENSMUSG00000053846 lipase, −3.0034782 −2.8106618 0.19281639 −3.0034782endothelial Acaa2 2.67619E−08 ENSMUSG00000036880 acetyl- −2.95471843.5845153 6.5392337 −2.9547184 Coenzyme A acyltransferase 2(mitochondrial 3-oxoacyl- Coenzyme A thiolase) 2410066E13Rik 0.012788476ENSMUSG00000038065 RIKEN cDNA −2.8722339 −4.3956246 −1.5233907−2.8722339 2410066E13 gene Dlg2 0.009360389 ENSMUSG00000052572 discs,large −2.8722338 −5.3956246 −2.5233908 −2.8722338 homolog 2 (Drosophila)2810405K02Rik 0.014735865 ENSMUSG00000029059 RIKEN cDNA −2.8722338−5.3956246 −2.5233908 −2.8722338 2810405K02 gene Gm20442 0.02830728ENSMUSG00000092600 predicted −2.8722338 −5.3956246 −2.5233908 −2.8722338gene 20442 Gja1 0.029196529 ENSMUSG00000050953 gap junction −2.8416021−0.3081615 2.5334406 −2.8416021 protein, alpha 1 Hist1h4n 0.029204158ENSMUSG00000069305 histone −2.8018444 −3.8106618 −1.0088174 −2.8018444cluster 1, H4n Cd28 0.034004346 ENSMUSG00000026012 CD28 antigen−2.8018444 −5.5476274 −2.745783 −2.8018444 Carns1 0.034741744ENSMUSG00000075289 carnosine −2.8018444 −5.5476274 −2.745783 −2.8018444synthase 1 Wnt9a 0.035009217 ENSMUSG00000000126 wingless-type −2.8018444−5.5476274 −2.745783 −2.8018444 MMTV integration site 9A Bcam0.035928585 ENSMUSG00000002980 basal cell −2.8018444 −5.5476274−2.745783 −2.8018444 adhesion molecule Emp1 0.042189736ENSMUSG00000030208 epithelial −2.7941766 3.9081564 6.702333 −2.7941766membrane protein 1 Parp16 0.04001856 ENSMUSG00000032392 poly (ADP-−2.7347302 −0.9361927 1.7985375 −2.7347302 ribose) polymerase family,member 16 Clcn7 0.03428333 ENSMUSG00000036636 chloride −2.72348935.0524917 7.775981 −2.7234893 channel 7 Eno2 0.03678912ENSMUSG00000004267 enolase 2, −2.7158498 1.080109 3.7959588 −2.7158498gamma neuronal Cbr3 0.019589162 ENSMUSG00000022947 carbonyl −2.6822627−0.9361927 1.74607 −2.6822627 reductase 3 Kdr 9.9922E−09ENSMUSG00000062960 kinase insert −2.6498416 −5.3956246 −2.745783−2.6498416 domain protein receptor Crip2 0.031184219 ENSMUSG00000006356cysteine rich −2.6498416 −5.3956246 −2.745783 −2.6498416 protein 2 Adcy50.032074198 ENSMUSG00000022840 adenylate −2.6498416 −5.3956246 −2.745783−2.6498416 cyclase 5 Tnfrsf25 0.037834987 ENSMUSG00000024793 tumor−2.6498416 −5.3956246 −2.745783 −2.6498416 necrosis factor receptorsuperfamily, member 25 Nacc2 1.90741E−05 ENSMUSG00000026932 nucleus−2.6016853 0.64876974 3.250455 −2.6016853 accumbens associated 2, BENand BTB (POZ) domain containing Vwf 0.007897177 ENSMUSG00000001930 Von−2.6009319 −3.0736964 −0.4727645 −2.6009319 Willebrand factor homologNpl 0.03968443 ENSMUSG00000042684 N- −2.5766314 0.6043756 3.181007−2.5766314 acetylneuraminate pyruvate lyase Tmprss11bnl 0.006505034ENSMUSG00000035861 transmembrane −2.53881 −5.5476274 −3.0088174 −2.53881protease, serine 11b N terminal like Gfi1b 0.006821152ENSMUSG00000026815 growth factor −2.53881 −5.5476274 −3.0088174 −2.53881independent 1B Gm9222 0.024540374 ENSMUSG00000091094 predicted −2.53881−5.5476274 −3.0088174 −2.53881 gene 9222 Scn5a 0.043510694ENSMUSG00000032511 sodium −2.53881 −5.5476274 −3.0088174 −2.53881channel, voltage- gated, type V, alpha Celf6 0.04390951ENSMUSG00000032297 CUGBP, Elav- −2.53881 −5.5476274 −3.0088174 −2.53881like family member 6 Gm6507 0.045192987 ENSMUSG00000090013 predicted−2.53881 −5.5476274 −3.0088174 −2.53881 gene 6507 Tm7sf4 0.03066966ENSMUSG00000022303 transmembrane 7 −2.538506 4.3441563 6.8826623−2.538506 superfamily member 4 Zbtb42 0.004560709 ENSMUSG00000037638zinc finger −2.5282794 −0.3512302 2.1770492 −2.5282794 and BTB domaincontaining 42 Oprl1 0.04202406 ENSMUSG00000027584 opioid −2.5243107−4.3956246 −1.8713139 −2.5243107 receptor-like 1 Smpd1 0.040762037ENSMUSG00000037049 sphingomyelin −2.4983536 2.8851464 5.3835 −2.4983536phosphodiesterase 1, acid lysosomal Copz2 0.04132218 ENSMUSG00000018672coatomer −2.4799163 −3.8106618 −1.3307455 −2.4799163 protein complex,subunit zeta 2 Rab13 0.014564358 ENSMUSG00000027935 RAB13, −2.4751628−1.1476969 1.3274659 −2.4751628 member RAS oncogene family Ltbp31.11691E−09 ENSMUSG00000024940 latent −2.4571964 −3.3956244 −0.938428−2.4571964 transforming growth factor beta binding protein 3 Traf50.005175546 ENSMUSG00000026637 TNF receptor- −2.4035177 1.29087633.694394 −2.4035177 associated factor 5 Rasgrp1 2.63666E−09ENSMUSG00000027347 RAS guanyl −2.3868072 −5.3956246 −3.0088174−2.3868072 releasing protein 1 Cyp3a41b 0.007969925 ENSMUSG00000075552cytochrome −2.3868072 −5.3956246 −3.0088174 −2.3868072 P450, family 3,subfamily a, polypeptide 41B H2-M10.4 0.008056933 ENSMUSG00000048231histocompatibility −2.3868072 −5.3956246 −3.0088174 −2.3868072 2, Mregion locus 10.4 Brsk1 0.013945078 ENSMUSG00000035390 BR −2.3868072−5.3956246 −3.0088174 −2.3868072 serine/threonine kinase 1 Comp0.019483332 ENSMUSG00000031849 cartilage −2.3868072 −5.3956246−3.0088174 −2.3868072 oligomeric matrix protein Trp53i11 1.85071E−07ENSMUSG00000068735 transformation −2.3868071 −3.0736964 −0.6868893−2.3868071 related protein 53 inducible protein 11 Gm17292 0.026323678ENSMUSG00000091500 predicted −2.3868071 −3.0736964 −0.6868893 −2.3868071gene, 17292 Tmem92- 0.012284395 ENSMUSG00000075610 transmembrane−2.3603347 −1.9361928 0.42414194 −2.3603347 ps protein 92, pseudogenePrnp 0.028792284 ENSMUSG00000079037 prion protein −2.3583783 0.96192773.320306 −2.3583783 Nos3 0.029377611 ENSMUSG00000028978 nitric oxide−2.3279133 −3.0736964 −0.7457831 −2.3279133 synthase 3, endothelial cellKifc3 0.02880698 ENSMUSG00000031788 kinesin family −2.3243729 2.59872914.923102 −2.3243729 member C3 D930049A15Rik 0.017146215ENSMUSG00000087535 RIKEN cDNA −2.3058869 −1.9361928 0.3696941 −2.3058869D930049A15 gene Dnajb13 0.04825035 ENSMUSG00000030708 DnaJ (Hsp40)−2.2872711 −3.8106618 −1.5233907 −2.2872711 related, subfamily B, member13 Ppargc1b 0.047570087 ENSMUSG00000033871 peroxisome −2.24670252.9352925 5.181995 −2.2467025 proliferative activated receptor, gamma,coactivator 1 beta Zan 0.046040762 ENSMUSG00000079173 zonadhesin−2.2348037 −2.8106618 −0.5758581 −2.2348037 Trpv4 2.0579E−08ENSMUSG00000014158 transient −2.2168817 −5.5476274 −3.3307457 −2.2168817receptor potential cation channel, subfamily V, member 4 Gm58785.70138E−08 ENSMUSG00000072952 predicted −2.2168817 −5.5476274−3.3307457 −2.2168817 gene 5878 Morn3 0.01710776 ENSMUSG00000029477 MORNrepeat −2.2168817 −5.5476274 −3.3307457 −2.2168817 containing 3 Ccdc1360.017162325 ENSMUSG00000029769 coiled-coil −2.2168817 −5.5476274−3.3307457 −2.2168817 domain containing 136 Pmel 0.0373233ENSMUSG00000025359 premelanosome −2.2168817 −5.5476274 −3.3307457−2.2168817 protein Exoc3l2 0.03821163 ENSMUSG00000011263 exocyst−2.2168817 −5.5476274 −3.3307457 −2.2168817 complex component 3- like 2Ctla4 0.04272519 ENSMUSG00000026011 cytotoxic T- −2.2168817 −5.5476274−3.3307457 −2.2168817 lymphocyte- associated protein 4 Eltd1 0.044563495ENSMUSG00000039167 EGF, −2.2168817 −5.5476274 −3.3307457 −2.2168817latrophilin seven transmembrane domain containing 1 Agap1 0.006535044ENSMUSG00000055013 ArfGAP with −2.2064753 2.5112662 4.7177415 −2.2064753GTPase domain, ankyrin repeat and PH domain 1 Gm16938 0.016329387ENSMUSG00000086325 predicted −2.2023824 −3.0736964 −0.871314 −2.2023824gene, 16938 BC043934 0.016358571 ENSMUSG00000056418 cDNA −2.1803559−2.8106618 −0.6303059 −2.1803559 sequence BC043934 Atp6v1g1 0.03608559ENSMUSG00000039105 ATPase, H+ −2.1788064 5.2264276 7.405234 −2.1788064transporting, lysosomal V1 subunit G1 Aebp1 1.28779E−07ENSMUSG00000020473 AE binding −2.1523415 −1.3956243 0.7567172 −2.1523415protein 1 Rgs10 2.5485E−06 ENSMUSG00000030844 regulator of −2.12283713.7207193 5.8435564 −2.1228371 G-protein signalling 10 Hist1h2be0.011067117 ENSMUSG00000047246 histone −2.1207322 −1.1476969 0.9730353−2.1207322 cluster 1, H2be Bcar1 0.005886043 ENSMUSG00000031955 breastcancer −2.1139732 0.6267435 2.7407167 −2.1139732 anti-estrogenresistance 1 2310035K24Rik 0.016051397 ENSMUSG00000068264 RIKEN cDNA−2.0865737 1.9706978 4.0572715 −2.0865737 2310035K24 gene Spata98.47829E−07 ENSMUSG00000021590 spermatogenesis −2.0648791 −4.3956246−2.3307455 −2.0648791 associated 9 Cdh24 0.003821577 ENSMUSG00000059674cadherin-like −2.0648791 −4.3956246 −2.3307455 −2.0648791 24 Ccr42.54713E−07 ENSMUSG00000047898 chemokine −2.0648789 −5.3956246−3.3307457 −2.0648789 (C-C motif) receptor 4 Trim15 5.39696E−05ENSMUSG00000050747 tripartite −2.0648789 −5.3956246 −3.3307457−2.0648789 motif- containing 15 Cntn2 0.003975537 ENSMUSG00000053024contactin 2 −2.0648789 −5.3956246 −3.3307457 −2.0648789 Pacsin30.004444425 ENSMUSG00000027257 protein −2.0648789 −5.3956246 −3.3307457−2.0648789 kinase C and casein kinase substrate in neurons 3 Ptch20.004492317 ENSMUSG00000028681 patched −2.0648789 −5.3956246 −3.3307457−2.0648789 homolog 2 Gm3086 0.004751403 ENSMUSG00000079076 predicted−2.0648789 −5.3956246 −3.3307457 −2.0648789 gene 3086 Gm135200.017877512 ENSMUSG00000052403 predicted −2.0648789 −5.3956246−3.3307457 −2.0648789 gene 13520 4831440E17Rik 0.047423657ENSMUSG00000091303 RIKEN cDNA −2.0648789 −5.3956246 −3.3307457−2.0648789 4831440E17 gene Olr1 0.02391179 ENSMUSG00000030162 oxidizedlow −2.0648788 −1.5882694 0.47660938 −2.0648788 density lipoprotein(lectin-like) receptor 1 Gpr68 0.014538036 ENSMUSG00000047415 G protein-−2.0587823 3.3013432 5.3601255 −2.0587823 coupled receptor 68 Speg0.016736077 ENSMUSG00000026207 SPEG −2.046822 2.2554274 4.3022494−2.046822 complex locus Rab11fip5 0.002548879 ENSMUSG00000051343 RAB11family −1.9835787 1.7942002 3.7777789 −1.9835787 interacting protein 5(class I) Kidins220 0.019567724 ENSMUSG00000036333 kinase D- −1.9395356.379986 8.319521 −1.939535 interacting substrate 220 Atp6v1e10.004245304 ENSMUSG00000019210 ATPase, H+ −1.9293203 4.4885464 6.4178667−1.9293203 transporting, lysosomal V1 subunit E1 Pvrl2 8.34206E−07ENSMUSG00000062300 poliovirus −1.9279968 0.4623566 2.3903534 −1.9279968receptor- related 2 Tspan17 1.0474E−07 ENSMUSG00000025875 tetraspanin−1.9204887 0.5816556 2.5021443 −1.9204887 17 Gale 0.019762464ENSMUSG00000028671 galactose-4- −1.8952713 1.7541227 3.649394 −1.8952713epimerase, UDP Rcan1 0.01904115 ENSMUSG00000022951 regulator of−1.874314 4.818695 6.693009 −1.874314 calcineurin 1 Gm11973 2.37392E−07ENSMUSG00000086839 predicted −1.8722338 −0.8106618 1.061572 −1.8722338gene 11973 Jag1 7.22295E−06 ENSMUSG00000027276 jagged 1 −1.86412864.084156 5.9482846 −1.8641286 Pkn3 0.008641912 ENSMUSG00000026785protein −1.861691 3.7566605 5.6183515 −1.861691 kinase N3 Gpr137b-0.037627038 ENSMUSG00000075118 G protein- −1.8487921 5.7122464 7.5610385−1.8487921 ps coupled receptor 137B, pseudogene Gpr137b 0.000425558ENSMUSG00000021306 G protein- −1.8473807 6.3339963 8.181377 −1.8473807coupled receptor 137B Fastk 0.025559984 ENSMUSG00000028959 Fas-activated−1.8316917 4.5629287 6.3946204 −1.8316917 serine/threonine kinase Fhod10.021275658 ENSMUSG00000014778 formin −1.83153 3.174231 5.005761−1.83153 homology 2 domain containing 1 Klf10 0.025064955ENSMUSG00000037465 Kruppel-like −1.8288834 2.3987916 4.227675 −1.8288834factor 10 Gm16170 0.025048712 ENSMUSG00000086245 predicted −1.8018444−3.8106618 −2.0088174 −1.8018444 gene 16170 Nrarp 6.95089E−07ENSMUSG00000078202 Notch- −1.8018444 −5.5476274 −3.745783 −1.8018444regulated ankyrin repeat protein Rab19 1.2671E−06 ENSMUSG00000029923RAB19, −1.8018444 −5.5476274 −3.745783 −1.8018444 member RAS oncogenefamily Hapln3 1.68935E−06 ENSMUSG00000030606 hyaluronan −1.8018444−5.5476274 −3.745783 −1.8018444 and proteoglycan link protein 3 Ccdc802.68412E−06 ENSMUSG00000022665 coiled-coil −1.8018444 −5.5476274−3.745783 −1.8018444 domain containing 80 Gm4841 3.87708E−06ENSMUSG00000068606 predicted −1.8018444 −5.5476274 −3.745783 −1.8018444gene 4841 4930412F09Rik 4.95275E−06 ENSMUSG00000085321 RIKEN cDNA−1.8018444 −5.5476274 −3.745783 −1.8018444 4930412F09 gene Gm76942.55599E−05 ENSMUSG00000079188 predicted −1.8018444 −5.5476274 −3.745783−1.8018444 gene 7694 Mesp2 0.000146221 ENSMUSG00000030543 mesoderm−1.8018444 −5.5476274 −3.745783 −1.8018444 posterior 2 Rnf1520.000155408 ENSMUSG00000047496 ring finger −1.8018444 −5.5476274−3.745783 −1.8018444 protein 152 Gad1-ps 0.000243773 ENSMUSG00000090665glutamic acid −1.8018444 −5.5476274 −3.745783 −1.8018444 decarboxylase1, pseudogene Syngr3 0.000536011 ENSMUSG00000007021 synaptogyrin 3−1.8018444 −5.5476274 −3.745783 −1.8018444 Lrrc69 0.000857033ENSMUSG00000023151 leucine rich −1.8018444 −5.5476274 −3.745783−1.8018444 repeat containing 69 Zfp352 0.000882844 ENSMUSG00000070902zinc finger −1.8018444 −5.5476274 −3.745783 −1.8018444 protein 352Mapk8ip1 0.001025129 ENSMUSG00000027223 mitogen- −1.8018444 −5.5476274−3.745783 −1.8018444 activated protein kinase 8 interacting protein 1Cplx2 0.001481371 ENSMUSG00000025867 complexin 2 −1.8018444 −5.5476274−3.745783 −1.8018444 2310005G13Rik 0.005757555 ENSMUSG00000046748 RIKENcDNA −1.8018444 −5.5476274 −3.745783 −1.8018444 2310005G13 gene Ndst30.00595649 ENSMUSG00000027977 N- −1.8018444 −5.5476274 −3.745783−1.8018444 deacetylase/ N- sulfotransferase (heparan glucosaminyl) 3Cdhr2 0.008793266 ENSMUSG00000034918 cadherin- −1.8018444 −5.5476274−3.745783 −1.8018444 related family member 2 Tac4 0.009837943ENSMUSG00000020872 tachykinin 4 −1.8018444 −5.5476274 −3.745783−1.8018444 Nexn 0.011523547 ENSMUSG00000039103 nexilin −1.8018444−5.5476274 −3.745783 −1.8018444 Usp17l5 0.013230624 ENSMUSG00000058976ubiquitin −1.8018444 −5.5476274 −3.745783 −1.8018444 specific peptidase17- like 5 9430020K01Rik 0.028962463 ENSMUSG00000033960 RIKEN cDNA−1.8018444 −5.5476274 −3.745783 −1.8018444 9430020K01 gene Rian0.032669194 ENSMUSG00000091793 RNA −1.8018444 −5.5476274 −3.745783−1.8018444 imprinted and accumulated in nucleus Fras1 0.03300434ENSMUSG00000034687 Fraser −1.8018444 −5.5476274 −3.745783 −1.8018444syndrome 1 homolog (human) Rasgrp2 0.038632754 ENSMUSG00000032946 RAS,guanyl −1.8018444 −5.5476274 −3.745783 −1.8018444 releasing protein 2Gcnt2 0.042023577 ENSMUSG00000021360 glucosaminyl −1.8018444 −5.5476274−3.745783 −1.8018444 (N-acetyl) transferase 2, I-branching enzymePcdhb19 0.042246673 ENSMUSG00000043313 protocadherin −1.8018444−5.5476274 −3.745783 −1.8018444 beta 19 Cpt1c 1.00434E−05ENSMUSG00000007783 carnitine −1.7653185 −3.3956244 −1.6303059 −1.7653185palmitoyltransferase 1c Tcirg1 2.59394E−05 ENSMUSG00000001750 T-cell,−1.759994 7.245976 9.00597 −1.759994 immune regulator 1, ATPase, H+transporting, lysosomal V0 protein A3 Dguok 0.030540211ENSMUSG00000014554 deoxyguanosine −1.7519393 0.24823192 2.0001712−1.7519393 kinase Rnasek 0.03223572 ENSMUSG00000040904 ribonuclease,−1.7483242 2.9923928 4.740717 −1.7483242 RNase K Tmem170 0.004925352ENSMUSG00000031953 transmembrane −1.7414716 0.53511304 2.2765846−1.7414716 protein 170 Cdkl4 2.17175E−05 ENSMUSG00000033966 cyclin-−1.7332573 −0.5882695 1.1449878 −1.7332573 dependent kinase-like 4AA386476 0.00223168 ENSMUSG00000074357 expressed −1.7169555 −2.5882695−0.871314 −1.7169555 sequence AA386476 Efemp2 4.01625E−05ENSMUSG00000024909 epidermal −1.7053364 −1.3081615 0.39717492 −1.7053364growth factor- containing fibulin-like extracellular matrix protein 2Atox1 0.00219727 ENSMUSG00000018585 ATX1 −1.6888047 2.2978625 3.9866672−1.6888047 (antioxidant protein 1) homolog 1 (yeast) Acot13 0.03344103ENSMUSG00000006717 acyl-CoA −1.655059 1.1279377 2.7829967 −1.655059thioesterase 13 Zfand5 0.041743267 ENSMUSG00000024750 zinc finger,−1.6533193 5.2987337 6.952053 −1.6533193 AN1-type domain 5 Gng86.13976E−05 ENSMUSG00000063594 guanine −1.6498416 −5.3956246 −3.745783−1.6498416 nucleotide binding protein (G protein), gamma 8 Ldb30.000180388 ENSMUSG00000021798 LIM domain −1.6498416 −5.3956246−3.745783 −1.6498416 binding 3 Tpm2 0.000303012 ENSMUSG00000028464tropomyosin −1.6498416 −4.3956246 −2.745783 −1.6498416 2, beta Mamstr0.001821696 ENSMUSG00000042918 MEF2 −1.6498416 −5.3956246 −3.745783−1.6498416 activating motif and SAP domain containing transcriptionalregulator 0610009L18Rik 0.020528933 ENSMUSG00000043644 RIKEN cDNA−1.6498416 −5.3956246 −3.745783 −1.6498416 0610009L18 gene Wdr960.032827605 ENSMUSG00000044948 WD repeat −1.6498416 −5.3956246 −3.745783−1.6498416 domain 96 E030010A14Rik 0.046596386 ENSMUSG00000048572 RIKENcDNA −1.6498416 −5.3956246 −3.745783 −1.6498416 E030010A14 gene Itih10.048211228 ENSMUSG00000006529 inter-alpha −1.6498416 −5.3956246−3.745783 −1.6498416 trypsin inhibitor, heavy chain 1 1600016N20Rik1.96971E−06 ENSMUSG00000025500 RIKEN cDNA −1.6498414 −3.3956244−1.745783 −1.6498414 1600016N20 gene AA543186 0.036252256ENSMUSG00000091706 expressed −1.6498413 −3.0736964 −1.4238551 −1.6498413sequence AA543186 Adc 0.004476923 ENSMUSG00000028789 arginine −1.6296634−0.8106618 0.8190016 −1.6296634 decarboxylase Sh3bgrl3 0.003731431ENSMUSG00000028843 SH3 domain −1.6179714 6.1131606 7.731132 −1.6179714binding glutamic acid- rich protein- like 3 B430212C06Rik 0.014717348ENSMUSG00000046415 RIKEN cDNA −1.6009319 −2.0736964 −0.4727645−1.6009319 B430212C06 gene Cblb 0.000721993 ENSMUSG00000022637 CasitasB- −1.5841252 2.6377988 4.221924 −1.5841252 lineage lymphoma bA530083I20Rik 0.000124989 ENSMUSG00000086343 RIKEN cDNA −1.5794521−2.5882695 −1.0088174 −1.5794521 A530083I20 gene Cyb561 0.02012645ENSMUSG00000019590 cytochrome −1.5761316 1.0473192 2.6234508 −1.5761316b-561 Uqcr10 0.034956805 ENSMUSG00000059534 ubiquinol- −1.54712513.6239665 5.1710916 −1.5471251 cytochrome c reductase, complex IIIsubunit X Cbx8 0.046324532 ENSMUSG00000025578 chromobox −1.53265780.15896448 1.6916223 −1.5326578 homolog 8 (Drosophila Pc class) Comtd10.000179086 ENSMUSG00000021773 catechol-O- −1.526407 3.57016 5.096567−1.526407 methyltransferase domain containing 1 B430203G13Rik0.000268071 ENSMUSG00000067356 RIKEN cDNA −1.5243105 −3.3956244−1.8713139 −1.5243105 B430203G13 gene Tenc1 0.00078725ENSMUSG00000037003 tensin like C1 −1.5243105 −3.3956244 −1.8713139−1.5243105 domain- containing phosphatase Fam71f2 0.04721271ENSMUSG00000079652 family with −1.5243105 −3.3956244 −1.8713139−1.5243105 sequence similarity 71, member F2 Gnas 0.002411892ENSMUSG00000027523 GNAS −1.5211316 5.855266 7.3763976 −1.5211316(guanine nucleotide binding protein, alpha stimulating) complex locusTsku 1.447E−05 ENSMUSG00000049580 tsukushi −1.5165749 −0.30816151.2084134 −1.5165749 B3galt4 2.46354E−05 ENSMUSG00000067370 UDP-−1.5096637 −1.2256994 0.28396425 −1.5096637 Gal:betaGlcNAc beta 1,3-galactosyltransferase, polypeptide 4 Actg1 6.26977E−05ENSMUSG00000062825 actin, −1.504394 8.558754 10.063148 −1.504394 gamma,cytoplasmic 1 Slc39a13 0.042252257 ENSMUSG00000002105 solute carrier−1.5026059 4.2978625 5.8004684 −1.5026059 family 39 (metal iontransporter), member 13 Pde8b 0.000171998 ENSMUSG00000021684phosphodiesterase −1.4957519 3.5321536 5.0279055 −1.4957519 8B Pla1a0.048690666 ENSMUSG00000002847 phospholipase −1.4945631 0.21908551.7136486 −1.4945631 A1 member A Ihh 0.000187296 ENSMUSG00000006538Indian −1.4799163 −3.8106618 −2.3307455 −1.4799163 hedgehog Bst10.027398707 ENSMUSG00000029082 bone marrow −1.4799163 1.9442257 3.424142−1.4799163 stromal cell antigen 1 Pmepa1 0.001784973 ENSMUSG00000038400prostate −1.4649818 3.0638072 4.528789 −1.4649818 transmembrane protein,androgen induced 1 Ostm1 0.000209975 ENSMUSG00000038280 osteopetrosis−1.4622026 4.755392 6.2175946 −1.4622026 associated transmembraneprotein 1 Pnkd 0.002613748 ENSMUSG00000026179 paroxysmal −1.4537571.9263037 3.3800607 −1.453757 nonkinesiogenic dyskinesia Aldoc0.031371355 ENSMUSG00000017390 aldolase C, −1.4523878 4.37421375.8266015 −1.4523878 fructose- bisphosphate Gpr157 0.002507451ENSMUSG00000047875 G protein- −1.4509373 1.0638072 2.5147445 −1.4509373coupled receptor 157 Itm2c 0.000136527 ENSMUSG00000026223 integral−1.4433904 5.314321 6.7577114 −1.4433904 membrane protein 2C Pld10.001237733 ENSMUSG00000027695 phospholipase −1.4425491 1.64876993.091319 −1.4425491 D1 Sun2 0.005151057 ENSMUSG00000042524 Sad1 and−1.4423764 4.701091 6.1434674 −1.4423764 UNC84 domain containing 2 Cdon0.018776068 ENSMUSG00000038119 cell adhesion −1.4239599 −0.87206240.55189747 −1.4239599 molecule- related/down- regulated by oncogenesCyp4f13 0.000314138 ENSMUSG00000024055 cytochrome −1.4210226 1.570162.9911826 −1.4210226 P450, family 4, subfamily f, polypeptide 13 Gcc10.002457876 ENSMUSG00000029708 golgi coiled −1.4146862 2.96192744.3766136 −1.4146862 coil 1 Grhpr 0.004643564 ENSMUSG00000035637glyoxylate −1.4079125 1.1742313 2.5821438 −1.4079125reductase/hydroxypyruvate reductase Traf6 0.04253863 ENSMUSG00000027164TNF receptor- −1.3917976 4.262587 5.6543846 −1.3917976 associated factor6 Plcg1 0.027477618 ENSMUSG00000016933 phospholipase −1.38751223.2803328 4.667845 −1.3875122 C, gamma 1 Gm711 0.000219044ENSMUSG00000049897 predicted −1.3868072 −4.3956246 −3.0088174 −1.3868072gene 711 Gpr182 0.001226294 ENSMUSG00000058396 G protein- −1.386807−3.3956244 −2.0088174 −1.386807 coupled receptor 182 D2hgdh 0.006610859ENSMUSG00000073609 D-2- −1.3820164 2.1042216 3.486238 −1.3820164hydroxyglutarate dehydrogenase Tmem19 0.001470068 ENSMUSG00000069520transmembrane −1.3742473 3.8874643 5.2617116 −1.3742473 protein 19Tmem120a 0.018098773 ENSMUSG00000039886 transmembrane −1.36981083.3987916 4.7686024 −1.3698108 protein 120A Tssk6 0.00016489ENSMUSG00000047654 testis-specific −1.3576605 −0.0736962 1.2839643−1.3576605 serine kinase 6 Camk1 7.14941E−05 ENSMUSG00000030272calcium/calmodulin- −1.351926 3.342468 4.694394 −1.351926 dependentprotein kinase I Mitf 0.001512894 ENSMUSG00000035158 microphthalmia-−1.350885 4.788011 6.138896 −1.350885 associated transcription factorHspa1b 0.000582485 ENSMUSG00000090877 heat shock −1.3323592 −0.64073690.69162226 −1.3323592 protein 1B Hyal2 0.04322722 ENSMUSG00000010047hyalurono- −1.3124657 3.4052758 4.7177415 −1.3124657 glucosaminidase 2Snapc5 0.001169527 ENSMUSG00000032398 small nuclear −1.3058869−0.3512302 0.95465666 −1.3058869 RNA activating complex, polypeptide 5Adcy9 0.000661473 ENSMUSG00000005580 adenylate −1.3011768 2.07198123.373158 −1.3011768 cyclase 9 Sh3bgrl 0.000909132 ENSMUSG00000031246SH3-binding −1.2961377 4.8391933 6.135331 −1.2961377 domain glutamicacid- rich protein like Trip10 0.03646866 ENSMUSG00000019487 thyroid−1.2951012 2.9035838 4.198685 −1.2951012 hormone receptor interactor 10Glis2 0.000204305 ENSMUSG00000014303 GLIS family −1.2872714 −2.2256994−0.938428 −1.2872714 zinc finger 2 4732465J04Rik 0.000652129ENSMUSG00000071107 RIKEN cDNA −1.287271 −3.8106618 −2.5233908 −1.2872714732465104 gene Dstn 0.009541933 ENSMUSG00000015932 destrin −1.28528776.1116743 7.396962 −1.2852877 Bad 0.03586843 ENSMUSG00000024959 BCL2-−1.2839432 2.1435344 3.4274776 −1.2839432 associated agonist of celldeath Cbr1 0.04490556 ENSMUSG00000051483 carbonyl −1.2796881 1.37255992.652248 −1.2796881 reductase 1 Cd180 0.04057961 ENSMUSG00000021624CD180 −1.2769055 5.7043805 6.981286 −1.2769055 antigen Kbtbd110.016952015 ENSMUSG00000055675 kelch repeat −1.2746457 6.5161427.7907877 −1.2746457 and BTB (POZ) domain containing 11 Rftn20.000334329 ENSMUSG00000025978 raftlin family −1.2743322 −1.3956243−0.1212921 −1.2743322 member 2 Bloc1s1 0.005817233 ENSMUSG00000090247biogenesis of −1.2713295 0.30481544 1.5761449 −1.2713295 lysosome-related organelles complex-1, subunit 1 Sdhc 0.009144416ENSMUSG00000058076 succinate −1.26805 5.124012 6.392062 −1.26805dehydrogenase complex, subunit C, integral membrane protein Fosl20.038066894 ENSMUSG00000029135 fos-like −1.265212 8.133928 9.39914−1.265212 antigen 2 Agap3 0.00044129 ENSMUSG00000023353 ArfGAP with−1.264696 5.073 6.337696 −1.264696 GTPase domain, ankyrin repeat and PHdomain 3 Gm16372 0.003350369 ENSMUSG00000057160 predicted −1.2619156−0.0380723 1.2238433 −1.2619156 pseudogene 16372 Pip5k1b 0.004221178ENSMUSG00000024867 phosphatidylinositol- −1.258926 5.6555843 6.9145103−1.258926 4- phosphate 5- kinase, type 1 beta Avpi1 0.034654055ENSMUSG00000018821 arginine −1.255085 2.6211839 3.8762689 −1.255085vasopressin- induced 1 Atp5j2 0.011021042 ENSMUSG00000038690 ATPsynthase, −1.2517338 3.8162642 5.067998 −1.2517338 H+ transporting,mitochondrial F0 complex, subunit F2 Cyc1 0.04513956 ENSMUSG00000022551cytochrome −1.2489853 5.1072073 6.3561926 −1.2489853 c-1 Tollip0.001564898 ENSMUSG00000025139 toll −1.2389507 4.1968327 5.4357834−1.2389507 interacting protein C330011M18Rik 0.000299532ENSMUSG00000056753 RIKEN cDNA −1.2348039 −3.3956244 −2.1608205−1.2348039 C330011M18 gene Fam108a 0.003468877 ENSMUSG00000003346 familywith −1.2336335 3.2873702 4.5210037 −1.2336335 sequence similarity 108,member A Gm11273 0.003542103 ENSMUSG00000079941 predicted −1.2310313.715511 4.946542 −1.231031 gene 11273 Abhd14a 0.001433305ENSMUSG00000042210 abhydrolase −1.2276082 0.67046493 1.8980731−1.2276082 domain containing 14A Pccb 0.000628514 ENSMUSG00000032527propionyl −1.2272532 2.8235443 4.0507975 −1.2272532 Coenzyme Acarboxylase, beta polypeptide Sbno2 0.001419982 ENSMUSG00000035673strawberry −1.223022 5.3650956 6.5881176 −1.223022 notch homolog 2(Drosophila) Yif1a 0.008634817 ENSMUSG00000024875 Yip1 −1.21789031.7642471 2.9821374 −1.2178903 interacting factor homolog A (S.cerevisiae) Pip5kl1 0.000696783 ENSMUSG00000046854 phosphatidylinositol-−1.2168817 −5.5476274 −4.3307457 −1.2168817 4- phosphate 5- kinase-like1 Tnfrsf17 0.001270444 ENSMUSG00000022496 tumor −1.2168817 −5.5476274−4.3307457 −1.2168817 necrosis factor receptor superfamily, member 17Slc10a6 0.00129448 ENSMUSG00000029321 solute carrier −1.2168817−5.5476274 −4.3307457 −1.2168817 family 10 (sodium/bile acidcotransporter family), member 6 Rhox2d 0.001357955 ENSMUSG00000079634reproductive −1.2168817 −5.5476274 −4.3307457 −1.2168817 homeobox 2DAdamts16 0.001422754 ENSMUSG00000049538 a disintegrin- −1.2168817−5.5476274 −4.3307457 −1.2168817 like and metallopeptidase (reprolysintype) with thrombospondin type 1 motif, 16 Adcy1 0.001623965ENSMUSG00000020431 adenylate −1.2168817 −5.5476274 −4.3307457 −1.2168817cyclase 1 4933402P03Rik 0.002350824 ENSMUSG00000044084 RIKEN cDNA−1.2168817 −5.5476274 −4.3307457 −1.2168817 4933402P03 gene Gm166190.002409908 ENSMUSG00000086303 predicted −1.2168817 −5.5476274−4.3307457 −1.2168817 gene, 16619 Crb3 0.002483939 ENSMUSG00000044279crumbs −1.2168817 −5.5476274 −4.3307457 −1.2168817 homolog 3(Drosophila) Fbxo17 0.002832668 ENSMUSG00000030598 F-box protein−1.2168817 −5.5476274 −4.3307457 4.2168817 17 Podnl1 0.003043215ENSMUSG00000012889 podocan-like 1 −1.2168817 −5.5476274 −4.3307457−1.2168817 Iglon5 0.003664683 ENSMUSG00000013367 IgLON family −1.2168817−5.5476274 −4.3307457 −1.2168817 member 5 Wdr16 0.004747208ENSMUSG00000020904 WD repeat −1.2168817 −5.5476274 −4.3307457 −1.2168817domain 16 Slc28a1 0.004920505 ENSMUSG00000025726 solute carrier−1.2168817 −5.5476274 −4.3307457 −1.2168817 family 28 (sodium- couplednucleoside transporter), member 1 Hspg2 0.005137672 ENSMUSG00000028763perlecan −1.2168817 −5.5476274 −4.3307457 −1.2168817 (heparan sulfateproteoglycan 2) Cpne9 0.005249562 ENSMUSG00000030270 copine family−1.2168817 −5.5476274 −4.3307457 −1.2168817 member IX Ttc23l 0.006339658ENSMUSG00000022249 tetratricopeptide −1.2168817 −5.5476274 −4.3307457−1.2168817 repeat domain 23- like Ppp1r1b 0.007002014 ENSMUSG00000061718protein −1.2168817 −5.5476274 −4.3307457 −1.2168817 phosphatase 1,regulatory (inhibitor) subunit 1B Acsbg2 0.007208475 ENSMUSG00000024207acyl-CoA −1.2168817 −5.5476274 −4.3307457 −1.2168817 synthetasebubblegum family member 2 Peli3 0.014013367 ENSMUSG00000024901 pellino 3−1.2168817 −5.5476274 −4.3307457 −1.2168817 Myo15b 0.018579457ENSMUSG00000034427 myosin XVB −1.2168817 −5.5476274 −4.3307457−1.2168817 Scn4a 0.018845024 ENSMUSG00000001027 sodium −1.2168817−5.5476274 −4.3307457 −1.2168817 channel, voltage- gated, type IV, alphaSh3bp4 0.021253621 ENSMUSG00000036206 SH3-domain −1.2168817 −5.5476274−4.3307457 −1.2168817 binding protein 4 Gcom1 0.02231107ENSMUSG00000041361 GRINL1A −1.2168817 −5.5476274 −4.3307457 −1.2168817complex locus Faim2 0.035814784 ENSMUSG00000023011 Fas apoptotic−1.2168817 −5.5476274 −4.3307457 −1.2168817 inhibitory molecule 2 Sox100.04996452 ENSMUSG00000033006 SRY-box −1.2168817 −5.5476274 −4.3307457−1.2168817 containing gene 10 Letm1 0.001400281 ENSMUSG00000005299leucine −1.207101 4.858223 6.065324 −1.207101 zipper-EF- hand containingtransmembrane protein 1 Obfc1 0.033878557 ENSMUSG00000042694oligonucleotide/ −1.2036425 3.3048155 4.508458 −1.2036425oligosaccharide- binding fold containing 1 Tnfaip3 0.002788399ENSMUSG00000019850 tumor −1.201921 4.3407774 5.5426984 −1.201921necrosis factor, alpha- induced protein 3 Gnpda1 0.01936977ENSMUSG00000052102 glucosamine- −1.1803564 4.0962286 5.276585 −1.18035646-phosphate deaminase 1 4921507L20Rik 0.000400257 ENSMUSG00000027196RIKEN cDNA −1.1803559 −2.8106618 −1.6303059 −1.1803559 4921507L20 geneGcnt7 0.002288528 ENSMUSG00000074569 glucosaminyl −1.1803559 −2.8106618−1.6303059 −1.1803559 (N-acetyl) transferase family member 7 Gm167140.005287915 ENSMUSG00000085339 predicted −1.1803559 −2.8106618−1.6303059 −1.1803559 gene, 16714 Gm10642 0.004257144 ENSMUSG00000074213predicted −1.1803559 0.18933822 1.3696941 −1.1803559 gene 10642 Kif5a0.003976241 ENSMUSG00000074657 kinesin family −1.1786551 3.44042594.619081 −1.1786551 member 5A Ucp2 0.018080156 ENSMUSG00000033685uncoupling −1.174402 8.331445 9.505847 −1.174402 protein 2(mitochondrial, proton carrier) Stx4a 0.001855345 ENSMUSG00000030805syntaxin 4A −1.1708516 4.2838554 5.454707 −1.1708516 (placental) Arpc40.04566701 ENSMUSG00000079426 actin related −1.1692152 6.64740327.8166184 −1.1692152 protein 2/3 complex, subunit 4 Tyrobp 0.006254981ENSMUSG00000030579 TYRO protein −1.1689372 6.1623178 7.331255 −1.1689372tyrosine kinase binding protein 1810014F10Rik 0.006210305ENSMUSG00000025466 RIKEN cDNA −1.1683084 1.813829 2.9821374 −1.16830841810014F10 gene Git1 0.017137151 ENSMUSG00000011877 G protein-−1.1681207 5.449866 6.6179867 −1.1681207 coupled receptor kinase-interactor 1 Hemk1 0.00164007 ENSMUSG00000032579 HemK −1.1644144−1.5882694 −0.423855 −1.1644144 methyltransferase family member 1 Akr7a50.001301134 ENSMUSG00000028743 aldo-keto −1.1609256 1.7129 2.8738256−1.1609256 reductase family 7, member A5 (aflatoxin aldehyde reductase)Gng7 0.011786759 ENSMUSG00000048240 guanine −1.1600361 −0.93619270.22384338 −1.1600361 nucleotide binding protein (G protein), gamma 7Lfng 0.002728639 ENSMUSG00000029570 LFNG O- −1.1599504 4.08010865.240059 −1.1599504 fucosylpeptide 3-beta-N- acetylglucosaminyl-transferase 4930481A15Rik 0.00970437 ENSMUSG00000086938 RIKEN cDNA−1.1568013 −0.1476968 1.0091045 −1.1568013 4930481A15 gene Sema4g0.009896757 ENSMUSG00000025207 sema domain, −1.1494124 1.46235662.611769 −1.1494124 immunoglobulin domain (Ig), transmembrane domain(TM) and short cytoplasmic domain, (semaphorin) 4G Eef2k 0.027855942ENSMUSG00000035064 eukaryotic −1.148943 2.248232 3.397175 −1.148943elongation factor-2 kinase Marveld1 0.01568347 ENSMUSG00000044345 MARVEL−1.1408279 3.5142686 4.6550965 −1.1408279 (membrane- associating) domaincontaining 1 Med29 0.000937494 ENSMUSG00000003444 mediator −1.13789362.1200755 3.2579691 −1.1378936 complex subunit 29 Ndufv1 0.004069016ENSMUSG00000037916 NADH −1.1364661 5.3525686 6.4890347 −1.1364661dehydrogenase (ubiquinone) flavoprotein 1 Idh3b 0.001815378ENSMUSG00000027406 isocitrate −1.1333637 5.6107016 6.7440653 −1.1333637dehydrogenase 3 (NAD+) beta Slc9a1 0.049830776 ENSMUSG00000028854 solutecarrier −1.1203177 3.5262167 4.6465344 −1.1203177 family 9(sodium/hydrogen exchanger), member 1 1110005A03Rik 0.011171196ENSMUSG00000090266 RIKEN cDNA −1.1139733 1.6267434 2.7407167 −1.11397331110005A03 gene Adamts10 0.003044179 ENSMUSG00000024299 a disintegrin-−1.107314 1.6704649 2.7777789 −1.107314 like and metallopeptidase(reprolysin type) with thrombospondin type 1 motif, 10 Atp5e 0.000939308ENSMUSG00000016252 ATP synthase, −1.1058641 3.9308052 5.0366693−1.1058641 H+ transporting, mitochondrial F1 complex, epsilon subunitSirt5 0.009139757 ENSMUSG00000054021 sirtuin 5 −1.103014 1.41173052.5147445 −1.103014 (silent mating type information regulation 2homolog) 5 (S. cerevisiae) 49305200O4Rik 0.012646059 ENSMUSG00000074039RIKEN cDNA −1.1023534 0.43726566 1.5396191 −1.1023534 4930520O04 genePydc4 0.02548906 ENSMUSG00000073491 pyrin domain −1.1018054 1.68119132.7829967 −1.1018054 containing 4 Nfatc1 0.002607991 ENSMUSG00000033016nuclear factor −1.0996833 7.4641047 8.563788 −1.0996833 of activatedT-cells, cytoplasmic, calcineurin- dependent 1 Sirt3 0.000476384ENSMUSG00000025486 sirtuin 3 −1.0970113 1.3987916 2.4958029 −1.0970113(silent mating type information regulation 2, homolog) 3 (S. cerevisiae)Nkain1 0.026548363 ENSMUSG00000078532 Na+/K+ −1.0950936 2.1666183.2617116 −1.0950936 transporting ATPase interacting 1 Tmem179b0.004654881 ENSMUSG00000079437 transmembrane −1.0883923 2.33908533.4274776 −1.0883923 protein 179B Egr1 0.011464391 ENSMUSG00000038418early growth −1.0853431 0.7336586 1.8190017 −1.0853431 response 1 Fdxr0.018414063 ENSMUSG00000018861 ferredoxin −1.0834726 3.332296 4.4157686−1.0834726 reductase Ptov1 0.003783276 ENSMUSG00000038502 prostate−1.076344 3.743927 4.820271 −1.076344 tumor over expressed gene 1 Nradd0.0219546 ENSMUSG00000032491 neurotrophin −1.0700967 1.7129 2.7829967−1.0700967 receptor associated death domain A230051G13Rik 0.031146139ENSMUSG00000049287 RIKEN cDNA −1.0672655 2.8427804 3.9100459 −1.0672655A230051G13 gene Gm9982 0.001856765 ENSMUSG00000055831 predicted−1.064879 −3.0736964 −2.0088174 −1.064879 gene 9982 Gm10645 0.004558912ENSMUSG00000074228 predicted −1.064879 −3.0736964 −2.0088174 −1.064879gene 10645 Tas1r3 0.005695173 ENSMUSG00000029072 taste −1.064879−2.0736964 −1.0088174 −1.064879 receptor, type 1, member 3 Adcy60.001144709 ENSMUSG00000022994 adenylate −1.0648789 −5.3956246−4.3307457 −1.0648789 cyclase 6 Rgs12 0.002267373 ENSMUSG00000029101regulator of −1.0648789 −3.3956244 −2.3307455 −1.0648789 G-proteinsignaling 12 Olfr212 0.002351982 ENSMUSG00000053251 olfactory −1.0648789−5.3956246 −4.3307457 −1.0648789 receptor 212 1700054O19Rik 0.004014643ENSMUSG00000057293 RIKEN cDNA −1.0648789 −5.3956246 −4.3307457−1.0648789 1700054O19 gene Ccdc67 0.007290532 ENSMUSG00000039977coiled-coil −1.0648789 −5.3956246 −4.3307457 −1.0648789 domaincontaining 67 C4b 0.008590216 ENSMUSG00000073418 complement −1.0648789−2.3956244 −1.3307455 −1.0648789 component 4B (Childo blood group)Arhgef17 0.009287045 ENSMUSG00000032875 Rho guanine −1.0648789−3.3956244 −2.3307455 −1.0648789 nucleotide exchange factor (GEF) 17Slc36a3 0.013117594 ENSMUSG00000049491 solute carrier −1.0648789−5.3956246 −4.3307457 −1.0648789 family 36 (proton/amino acidsymporter), member 3 Gm20468 0.013459157 ENSMUSG00000092539 predicted−1.0648789 −5.3956246 −4.3307457 −1.0648789 gene 20468 4930455G09Rik0.013695496 ENSMUSG00000085761 RIKEN cDNA −1.0648789 −3.3956244−2.3307455 −1.0648789 4930455G09 gene Wap 0.01899181 ENSMUSG00000000381whey acidic −1.0648789 −5.3956246 −4.3307457 −1.0648789 protein Ccdc540.028815286 ENSMUSG00000050685 coiled-coil −1.0648789 −5.3956246−4.3307457 −1.0648789 domain containing 54 Tmem130 0.03130156ENSMUSG00000043388 transmembrane −1.0648789 −5.3956246 −4.3307457−1.0648789 protein 130 Nrcam 0.045242175 ENSMUSG00000020598 neuron-glia-−1.0648789 −5.3956246 −4.3307457 −1.0648789 CAM-related cell adhesionmolecule Bfsp2 0.006345339 ENSMUSG00000032556 beaded −1.0648789−4.3956246 −3.3307457 −1.0648789 filament structural protein 2, phakininRab27b 0.007012791 ENSMUSG00000024511 RAB27b, −1.0648789 −4.3956246−3.3307457 −1.0648789 member RAS oncogene family Aqp7 0.017064577ENSMUSG00000028427 aquaporin 7 −1.0648789 −4.3956246 −3.3307457−1.0648789 4930451E10Rik 0.01750742 ENSMUSG00000069223 RIKEN cDNA−1.0648789 −4.3956246 −3.3307457 −1.0648789 4930451E10 gene Ms4a4b0.03696975 ENSMUSG00000056290 membrane- −1.0648789 −4.3956246 −3.3307457−1.0648789 spanning 4- domains, subfamily A, member 4B 4930529M08Rik0.037663873 ENSMUSG00000037143 RIKEN cDNA −1.0648789 −4.3956246−3.3307457 −1.0648789 4930529M08 gene Rab11fip4 0.01102629ENSMUSG00000017639 RAB11 family −1.0648788 −3.8106618 −2.745783−1.0648788 interacting protein 4 (class II) 41887 0.016744798ENSMUSG00000072214 septin 5 −1.0648788 −3.8106618 −2.745783 −1.0648788Prx 0.016224083 ENSMUSG00000053198 periaxin −1.0648788 −2.2256994−1.1608206 −1.0648788 Dlec1 0.03235247 ENSMUSG00000038060 deleted in−1.0648788 −1.5882694 −0.5233907 −1.0648788 lung and esophageal cancer 1Rpl10a- 0.017712247 ENSMUSG00000061988 ribosomal −1.0648787 1.99669313.0615718 −1.0648787 ps2 protein L10A, pseudogene 2 Cyfip2 0.009189907ENSMUSG00000020340 cytoplasmic −1.0582762 2.3791628 3.437439 −1.0582762FMR1 interacting protein 2 Fgd6 0.005464029 ENSMUSG00000020021 FYVE,RhoGEF −1.0570075 4.296119 5.3531265 −1.0570075 and PH domain containing6 Spef1 0.006124181 ENSMUSG00000027329 sperm −1.0517034 0.385735361.4374388 −1.0517034 flagellar 1 Rab34 0.023153191 ENSMUSG00000002059RAB34, −1.0480704 2.6211839 3.6692543 −1.0480704 member of RAS oncogenefamily Klc2 0.001976282 ENSMUSG00000024862 kinesin light −1.04170252.5759192 3.6176217 −1.0417025 chain 2 Slc2a4 0.006559952ENSMUSG00000018566 solute carrier −1.0406312 −0.4887338 0.55189747−1.0406312 family 2 (facilitated glucose transporter), member 4 Map2k30.003899702 ENSMUSG00000018932 mitogen- −1.0403227 6.526588 7.5669107−1.0403227 activated protein kinase kinase 3 Dad1 0.00630479ENSMUSG00000022174 defender −1.0402053 4.695811 5.7360163 −1.0402053against cell death 1 Gm14455 0.004350234 ENSMUSG00000087633 predicted−1.0397879 −0.5376434 0.50214446 −1.0397879 gene 14455 Ak3 0.006733093ENSMUSG00000024782 adenylate −1.0376728 4.4340982 5.471771 −1.0376728kinase 3 Glce 0.007387917 ENSMUSG00000032252 glucuronyl −1.0325523.6239665 4.6565185 −1.032552 C5-epimerase Mtap7d1 0.00833793ENSMUSG00000028849 microtubule- −1.031302 5.0462823 6.0775843 −1.031302associated protein 7 domain containing 1 Ulk3 0.002965013ENSMUSG00000032308 unc-51-like −1.0307307 2.022228 3.0529587 −1.0307307kinase 3 (C. elegans) Ppap2c 0.01108149 ENSMUSG00000052151 phosphatidic−1.0295459 2.8805 3.9100459 −1.0295459 acid phosphatase type 2C Anapc20.001523701 ENSMUSG00000026965 anaphase −1.0289692 4.8331943 5.8621635−1.0289692 promoting complex subunit 2 Aldoart1 0.013166931ENSMUSG00000059343 aldolase 1A −1.028117 5.360098 6.388215 −1.028117retrogene 1 N4bp3 0.039391436 ENSMUSG00000001053 NEDD4 −1.0253504−0.186171 0.83917946 −1.0253504 binding protein 3 Repin1 0.00851355ENSMUSG00000052751 replication −1.0077979 1.4623566 2.4701545 −1.0077979initiator 1 Nudt14 0.003012999 ENSMUSG00000002804 nudix −1.00529012.0390038 3.0442939 −1.0052901 (nucleoside diphosphate linked moietyX)-type motif 14 A830007P12Rik 0.020650838 ENSMUSG00000059555 RIKEN cDNA−0.9985294 4.9001446 5.898674 −0.9985294 A830007P12 gene Aldoa0.002948088 ENSMUSG00000030695 aldolase A, −0.983461 8.502977 9.486438−0.983461 fructose- bisphosphate Arc 0.016652526 ENSMUSG00000022602activity −0.9824167 −1.2256994 −0.2432828 −0.9824167 regulatedcytoskeletal- associated protein Rgl2 0.008882542 ENSMUSG00000041354 ralguanine −0.979752 5.2135544 6.1933064 −0.979752 nucleotide dissociationstimulator- like 2 Shpk 0.019699099 ENSMUSG00000005951 sedoheptulokinase−0.9781672 0.5112662 1.4894334 −0.9781672 Aga 0.00395918ENSMUSG00000031521 aspartylglucosaminidase −0.9780013 1.87116222.8491635 −0.9780013 C230037L18Rik 0.016271891 ENSMUSG00000084915 RIKENcDNA −0.977416 −1.3081615 −0.3307455 −0.977416 C230037L18 gene Il17rc0.018987024 ENSMUSG00000030281 interleukin 17 −0.9750822 0.46235661.4374388 −0.9750822 receptor C Ocel1 0.019482028 ENSMUSG00000002396occludin/ELL −0.9746046 2.8570411 3.8316457 −0.9746046 domain containing1 Il1rn 0.004778137 ENSMUSG00000026981 interleukin 1 −0.973403 4.18369155.1570945 −0.973403 receptor antagonist Rps16 0.04162411ENSMUSG00000037563 ribosomal −0.97321 6.446333 7.419543 −0.97321 proteinS16 Zfp882 0.008488793 ENSMUSG00000089857 zinc finger −0.9717693−2.3956244 −1.4238551 −0.9717693 protein 882 Pold4 0.008677183ENSMUSG00000024854 polymerase −0.9683707 1.0137666 1.9821373 −0.9683707(DNA- directed), delta 4 Man2b1 0.04088014 ENSMUSG00000005142mannosidase −0.9667725 5.0232825 5.990055 −0.9667725 2, alpha B1 Athl10.00759034 ENSMUSG00000062031 ATH1, acid −0.9665135 3.3857355 4.352249−0.9665135 trehalase-like 1 (yeast) Fam195b 0.012424714ENSMUSG00000061111 family with −0.9629592 4.3971663 5.3601255 −0.9629592sequence similarity 195, member B Mtfp1 0.046913996 ENSMUSG00000004748mitochondrial −0.9624316 1.5585719 2.5210035 −0.9624316 fission process1 Cyb561d2 0.010208104 ENSMUSG00000037190 cytochrome −0.95901022.3322961 3.2913063 −0.9590102 b-561 domain containing 2 Tnfrsf11a0.010830157 ENSMUSG00000026321 tumor −0.958003 6.045245 7.003248−0.958003 necrosis factor receptor superfamily, member 11a 9230115E21Rik0.010104352 ENSMUSG00000074354 RIKEN cDNA −0.9579636 −2.5882695−1.6303059 −0.9579636 9230115E21 gene Adamts1 0.022076081ENSMUSG00000022893 a disintegrin- −0.9579636 −2.5882695 −1.6303059−0.9579636 like and metallopeptidase (reprolysin type) withthrombospondin type 1 motif, 1 Kif7 0.027391762 ENSMUSG00000050382kinesin family −0.9579635 −1.5882694 −0.6303059 −0.9579635 member 7Capn12 0.012989306 ENSMUSG00000054083 calpain 12 −0.9565671 2.91725853.8738256 −0.9565671 Gm16896 0.020594148 ENSMUSG00000085988 predicted−0.9511457 2.8805 3.8316457 −0.9511457 gene, 16896 Naga 0.004612528ENSMUSG00000022453 N-acetyl −0.9453887 3.7966683 4.742057 −0.9453887galactosaminidase, alpha Aagab 0.045944124 ENSMUSG00000037257 alpha- and−0.9409665 5.1141505 6.055117 −0.9409665 gamma- adaptin binding proteinGm2895 0.013068641 ENSMUSG00000091412 predicted −0.9393479 −2.8106618−1.8713139 −0.9393479 gene 2895 Ccdc90a 0.012132604 ENSMUSG00000021371coiled-coil −0.9371602 3.0962288 4.033389 −0.9371602 domain containing90A Rgs11 0.011104016 ENSMUSG00000024186 regulator of −0.93277520.9263038 1.859079 −0.9327752 G-protein signaling 11 Hyi 0.028181328ENSMUSG00000006395 hydroxypyruvate −0.9299492 0.99669313 1.9266423−0.9299492 isomerase homolog (E. coli) Gpr137 0.049236804ENSMUSG00000024958 G protein- −0.9295592 3.1082015 4.0377607 −0.9295592coupled receptor 137 Ndufs3 0.006582539 ENSMUSG00000005510 NADH−0.9273753 3.8451672 4.7725425 −0.9273753 dehydrogenase (ubiquinone)Fe—S protein 3 Acot11 0.010169235 ENSMUSG00000034853 acyl-CoA −0.92192080.3322961 1.2542169 −0.9219208 thioesterase 11 Cirbp 0.03442582ENSMUSG00000045193 cold inducible −0.919633 3.076051 3.995684 −0.919633RNA binding protein Acvrl1 0.017487064 ENSMUSG00000000530 activin A−0.9193378 2.2337322 3.15307 −0.9193378 receptor, type II-like 1 Ccdc1140.036372237 ENSMUSG00000040189 coiled-coil −0.919028 −0.69518460.22384338 −0.919028 domain containing 114 Snn 0.013385386ENSMUSG00000037972 stannin −0.9128759 −3.0736964 −2.1608205 −0.9128759Msi1 0.014250691 ENSMUSG00000054256 Musashi −0.9128759 −3.0736964−2.1608205 −0.9128759 homolog 1(Drosophila) Cyth1 0.048440345ENSMUSG00000017132 cytohesin 1 −0.9122796 2.675838 3.5881176 −0.9122796Aldh16a1 0.027805215 ENSMUSG00000007833 aldehyde −0.909904 4.68119145.5910954 −0.909904 dehydrogenase 16 family, member A1 Rsph3a0.011015884 ENSMUSG00000073471 radial spoke −0.9093094 2.41815663.327466 −0.9093094 3A homolog (Chlamydomonas) Commd4 0.008752169ENSMUSG00000032299 COMM −0.908303 2.9081564 3.8164594 −0.908303 domaincontaining 4 Flcn 0.008794582 ENSMUSG00000032633 folliculin −0.90668364.4716544 5.378338 −0.9066836 1700020I14Rik 0.002356395ENSMUSG00000085438 RIKEN cDNA −0.9060127 4.241 5.1470127 −0.90601271700020I14 gene Cd59b 0.009062648 ENSMUSG00000068686 CD59b −0.8977688−0.3956244 0.50214446 −0.8977688 antigen Gm15489 0.014427851ENSMUSG00000086942 predicted −0.8949539 −2.2256994 −1.3307455 −0.8949539gene 15489 Taf10 0.016606517 ENSMUSG00000043866 TAF10 RNA −0.89434954.8247538 5.7191033 −0.8943495 polymerase II, TATA box binding protein(TBP)- associated factor Eif2c4 0.011220387 ENSMUSG00000042500eukaryotic −0.8931125 2.804048 3.6971605 −0.8931125 translationinitiation factor 2C, 4 2810422J05Rik 0.002751657 ENSMUSG00000055553RIKEN cDNA −0.892449 7.259236 8.151685 −0.892449 2810422J05 geneAldoart2 0.014008217 ENSMUSG00000063129 aldolase 1 A −0.889758 4.0095174.899275 −0.889758 retrogene 2 Fbrsl1 0.020696755 ENSMUSG00000043323fibrosin-like 1 −0.8856542 2.3458426 3.2314968 −0.8856542 Suv420h20.034955982 ENSMUSG00000059851 suppressor of −0.8856541 3.66777094.553425 −0.8856541 variegation 4- 20 homolog 2 (Drosophila) Rgs140.008254785 ENSMUSG00000052087 regulator of −0.8804542 0.248231921.1286861 −0.8804542 G-protein signaling 14 Dhx34 0.016695064ENSMUSG00000006019 DEAH (Asp- −0.8802828 3.1855762 4.065859 −0.8802828Glu-Ala-His) box polypeptide 34 Orai2 0.01243197 ENSMUSG00000039747 ORAIcalcium −0.8786246 4.897847 5.7764716 −0.8786246 release- activatedcalcium modulator 2 Cope 0.015722413 ENSMUSG00000055681 coatomer−0.8782422 3.4020374 4.2802796 −0.8782422 protein complex, subunitepsilon Gm3550 0.006914831 ENSMUSG00000078240 predicted −0.87672662.4435794 3.320306 −0.8767266 gene 3550 Tspyl1 0.010131083ENSMUSG00000047514 testis-specific −0.8765944 5.1190896 5.995684−0.8765944 protein, Y- encoded-like 1 1810013L24Rik 0.008725129ENSMUSG00000022507 RIKEN cDNA −0.876027 5.614204 6.490231 −0.8760271810013L24 gene D4Wsu53e 0.008402507 ENSMUSG00000037266 DNA −0.87593326.209855 7.0857882 −0.8759332 segment, Chr 4, Wayne State University 53,expressed Ttn 0.006356048 ENSMUSG00000051747 titin −0.8746564 1.01376661.888423 −0.8746564 Tmem192 0.029768782 ENSMUSG00000025521 transmembrane−0.8737595 3.6811912 4.5549507 −0.8737595 protein 192 Gm6189 0.006221308ENSMUSG00000090637 predicted −0.8722337 −1.8106617 −0.938428 −0.8722337gene 6189 Atp6ap2 0.035808034 ENSMUSG00000031007 ATPase, H+ −0.8720287.740566 8.612594 −0.872028 transporting, lysosomal accessory protein 2Zfp524 0.03309677 ENSMUSG00000051184 zinc finger −0.8684815 0.385735361.2542169 −0.8684815 protein 524 Pgls 0.016186675 ENSMUSG00000031807 6-−0.8678807 4.4197593 5.28764 −0.8678807 phosphogluconolactonase Nhlrc30.044700302 ENSMUSG00000042997 NHL repeat −0.8672788 3.1551225 4.0224013−0.8672788 containing 3 Slc9a5 0.017414166 ENSMUSG00000014786 solutecarrier −0.8671144 2.523239 3.3903534 −0.8671144 family 9(sodium/hydrogen exchanger), member 5 Ctsz 0.025800172ENSMUSG00000016256 cathepsin Z −0.8654295 8.136001 9.0014305 −0.8654295Rps15 0.015647907 ENSMUSG00000063457 ribosomal −0.8634447 5.68386036.547305 −0.8634447 protein S15 Gaa 0.040927023 ENSMUSG00000025579glucosidase, −0.85985 5.17518 6.03503 −0.85985 alpha, acid Map3k100.011791729 ENSMUSG00000040390 mitogen- −0.8566368 2.1435344 3.0001712−0.8566368 activated protein kinase kinase kinase 10 Zfp526 0.029923318ENSMUSG00000046541 zinc finger −0.8533748 2.4561245 3.3094993 −0.8533748protein 526 Hist1h3g 0.014537657 ENSMUSG00000062417 histone −0.8491501−1.2256994 −0.3765493 −0.8491501 cluster 1, H3g Gm6055 0.032020975ENSMUSG00000062081 predicted −0.8490165 4.051459 4.9004755 −0.8490165gene 6055 C030037D09Rik 0.044817787 ENSMUSG00000087574 RIKEN cDNA−0.8468781 0.9619277 1.8088058 −0.8468781 C030037D09 gene Zswim70.026769519 ENSMUSG00000014243 zinc finger, −0.8460816 1.98807992.8341615 −0.8460816 SWIM-type containing 7 F420014N23Rik 0.017114388ENSMUSG00000086597 RIKEN cDNA −0.8444889 0.5112662 1.3557551 −0.8444889F420014N23 gene Ndufa9 0.005276035 ENSMUSG00000000399 NADH −0.8439575.205218 6.049175 −0.843957 dehydrogenase (ubiquinone) 1 alphasubcomplex, 9 Nr4a2 0.012531522 ENSMUSG00000026826 nuclear −0.84248641.1121702 1.9546566 −0.8424864 receptor subfamily 4, group A, member 2Gm20422 0.032568794 ENSMUSG00000092544 predicted −0.8424863 −0.00330690.83917946 −0.8424863 gene 20422 Map2k6 0.02493559 ENSMUSG00000020623mitogen- −0.8424863 −1.5882694 −0.7457831 −0.8424863 activated proteinkinase kinase 6 Ulk1 0.02368065 ENSMUSG00000029512 Unc-51 like−0.8396657 2.6043756 3.4440413 −0.8396657 kinase 1 (C. elegans) Slc39a30.01765952 ENSMUSG00000046822 solute carrier −0.8366098 1.96192772.7985375 −0.8366098 family 39 (zinc transporter), member 3 Tbc1d230.022578219 ENSMUSG00000022749 TBC1 domain −0.8355326 5.44751176.2830443 −0.8355326 family, member 23 Commd7 0.023516493ENSMUSG00000056941 COMM −0.8331583 3.7233167 4.556475 −0.8331583 domaincontaining 7 Gm6410 0.046976738 ENSMUSG00000090435 predicted −0.8304137−2.0736964 −1.2432827 −0.8304137 gene 6410 1110032A03Rik 0.019316237ENSMUSG00000037971 RIKEN cDNA −0.8304134 −0.0736962 0.7567172 −0.83041341110032A03 gene Pias4 0.04347021 ENSMUSG00000004934 protein −0.82407432.9352925 3.7593668 −0.8240743 inhibitor of activated STAT 4 Zkscan40.02395805 ENSMUSG00000054931 zinc finger −0.8238707 −0.11022210.7136486 −0.8238707 with KRAB and SCAN domains 4 Tlcd2 0.02366598ENSMUSG00000038217 TLC domain −0.8175689 0.7942001 1.611769 −0.8175689containing 2 Rap2a 0.018936511 ENSMUSG00000051615 RAS related −0.81426812.1357572 2.9500253 −0.8142681 protein 2a Snx7 0.01534647ENSMUSG00000028007 sorting nexin 7 −0.8141116 3.4020374 4.216149−0.8141116 Nfam1 0.011470164 ENSMUSG00000058099 Nfat −0.813933 4.4608015.274734 −0.813933 activating molecule with ITAM motif 1 Paqr30.025071675 ENSMUSG00000055725 progestin and −0.8123367 2.70240783.5147445 −0.8123367 adipoQ receptor family member III Orai2-ps0.02500956 ENSMUSG00000090850 ORAI calcium −0.8119425 3.6838605 4.495803−0.8119425 release- activated calcium modulator 2, pseudogene Epn20.017489249 ENSMUSG00000001036 epsin 2 −0.8102112 4.6623673 5.4725785−0.8102112 Bcl7b 0.035148133 ENSMUSG00000029681 B-cell −0.80955222.9966931 3.8062453 −0.8095522 CLL/lymphoma 7B 3110056O03Rik 0.033237558ENSMUSG00000035206 RIKEN cDNA −0.8087448 2.7942002 3.602945 −0.80874483110056O03 gene Mrpl22 0.048313465 ENSMUSG00000020514 mitochondrial−0.8068106 1.4623566 2.2691672 −0.8068106 ribosomal protein L22 Relt0.013668023 ENSMUSG00000008318 RELT tumor −0.8055995 2.8664703 3.6720698−0.8055995 necrosis factor receptor Naaladl1 0.043300908ENSMUSG00000054999 N-acetylated −0.8018445 −1.4887338 −0.6868893−0.8018445 alpha-linked acidic dipeptidase- like 1 Mtss1l 0.010499953ENSMUSG00000033763 metastasis −0.8018444 −2.8106618 −2.0088174−0.8018444 suppressor 1- like 1600029O15Rik 0.015520786ENSMUSG00000057818 RIKEN cDNA −0.8018444 −3.8106618 −3.0088174−0.8018444 1600029O15 gene Dao 0.024370153 ENSMUSG00000042096 D-aminoacid −0.8018444 −3.8106618 −3.0088174 −0.8018444 oxidase BC1253320.025244432 ENSMUSG00000041358 cDNA −0.8018444 −3.8106618 −3.0088174−0.8018444 sequence BC125332 Fat2 0.035712436 ENSMUSG00000055333 FATtumor −0.8018444 −3.8106618 −3.0088174 −0.8018444 suppressor homolog 2(Drosophila) Cabp7 0.033022203 ENSMUSG00000009075 calcium −0.8018443−1.8106617 −1.0088174 −0.8018443 binding protein 7 Gm7353 0.019511756ENSMUSG00000055452 predicted −0.8002038 3.6487699 4.4489737 −0.8002038pseudogene 7353 Rps8-ps1 0.014286589 ENSMUSG00000071303 ribosomal−0.799268 6.457295 7.256563 −0.799268 protein S8, pseudogene 1 Alcam0.02590528 ENSMUSG00000022636 activated −0.798258 5.32889 6.127148−0.798258 leukocyte cell adhesion molecule Fos 0.044314757ENSMUSG00000021250 FBJ −0.7970984 5.28737 6.0844684 −0.7970984osteosarcoma oncogene Mtss1 0.036628574 ENSMUSG00000022353 metastasis−0.796156 5.59377 6.389926 −0.796156 suppressor 1 Pcyox1 0.020175328ENSMUSG00000029998 prenylcysteine −0.7958059 4.2732606 5.0690665−0.7958059 oxidase 1 Rnaseh2c 0.022177652 ENSMUSG00000024925ribonuclease −0.7937506 1.7642471 2.5579977 −0.7937506 H2, subunit CTab1 0.01681519 ENSMUSG00000022414 TGF-beta −0.7932696 3.26615384.0594234 −0.7932696 activated kinase 1/MAP3K7 binding protein 1 Rps30.032059707 ENSMUSG00000030744 ribosomal −0.7917607 7.8012853 8.593046−0.7917607 protein S3 Gm5507 0.027941754 ENSMUSG00000069376 predicted−0.7911568 5.7220187 6.5131755 −0.7911568 gene 5507 Mrp63 0.014859019ENSMUSG00000021967 mitochondrial −0.7907952 3.1240118 3.914807−0.7907952 ribosomal protein 63 Solh 0.027924877 ENSMUSG00000037326small optic −0.7896872 3.3492093 4.1388965 −0.7896872 lobes homolog(Drosophila) Adamts13 0.02814318 ENSMUSG00000014852 a disintegrin-−0.7888179 2.6650715 3.4538894 −0.7888179 like and metallopeptidase(reprolysin type) with thrombospondin type 1 motif, 13 Lsm4 0.020239143ENSMUSG00000031848 LSM4 −0.7882819 3.6071906 4.3954725 −0.7882819homolog, U6 small nuclear RNA associated (S. cerevisiae) Triobp0.014277731 ENSMUSG00000033088 TRIO and F- −0.7874437 3.3955383 4.182982−0.7874437 actin binding protein Gm16156 0.012805327 ENSMUSG00000087436predicted −0.787345 1.5112662 2.2986112 −0.787345 gene 16156 Kcnn40.024224881 ENSMUSG00000054342 potassium −0.784895 5.302212 6.087107−0.784895 intermediate/ small conductance calcium- activated channel,subfamily N, member 4 Trmt61a 0.028067956 ENSMUSG00000060950 tRNA−0.783203 4.398792 5.181995 −0.783203 methyltransferase 61 homolog A (S.cerevisiae) Tpra1 0.032772 ENSMUSG00000002871 transmembrane −0.78175332.1589644 2.9407177 −0.7817533 protein, adipocyte asscociated 1 Adck40.028475156 ENSMUSG00000003762 aarF domain −0.779902 2.9172585 3.6971605−0.779902 containing kinase 4 Zfp189 0.02446675 ENSMUSG00000039634 zincfinger −0.7799019 0.3322961 1.112198 −0.7799019 protein 189 Trak20.029910393 ENSMUSG00000026028 trafficking −0.778933 5.470109 6.249042−0.778933 protein, kinesin binding 2 Setd4 0.039261803ENSMUSG00000022948 SET domain −0.7753723 2.0638072 2.8391795 −0.7753723containing 4 Ttc38 0.015144606 ENSMUSG00000035944 tetratricopeptide−0.773416 1.54689 2.320306 −0.773416 repeat domain 38 Ccdc88c 0.02540553ENSMUSG00000021182 coiled-coil −0.7721902 3.7842848 4.556475 −0.7721902domain containing 88C Gm10159 0.017318606 ENSMUSG00000069972 predicted−0.770136 5.800363 6.570499 −0.770136 pseudogene 10159 Aim1 0.02232682ENSMUSG00000019866 absent in −0.7701057 5.5120173 6.282123 −0.7701057melanoma 1 Rab11b 0.034848575 ENSMUSG00000077450 RAB11B, −0.76919374.3492093 5.118403 −0.7691937 member RAS oncogene family Leprot0.02571553 ENSMUSG00000035212 leptin −0.7679413 3.4654624 4.2334037−0.7679413 receptor overlapping transcript Agap2 0.020851009ENSMUSG00000025422 ArfGAP with −0.7653184 −1.3956243 −0.6303059−0.7653184 GTPase domain, ankyrin repeat and PH domain 2 Fbxl150.026200434 ENSMUSG00000025226 F-box and −0.7637091 0.71290016 1.4766093−0.7637091 leucine-rich repeat protein 15 Gm12942 0.024523953ENSMUSG00000070737 predicted −0.7623158 0.81382906 1.5761449 −0.7623158gene 12942 Pts 0.025246479 ENSMUSG00000032067 6-pyruvoyl- −0.76048492.1279378 2.8884227 −0.7604849 tetrahydropterin synthase 1110019D14Rik0.027602369 ENSMUSG00000084931 RIKEN cDNA −0.7600241 −0.00330690.7567172 −0.7600241 1110019D14 gene B230312A22Rik 0.015634464ENSMUSG00000036002 RIKEN cDNA −0.7591951 3.7413666 4.5005617 −0.7591951B230312A22 gene Pik3r1 0.012770501 ENSMUSG00000041417phosphatidylinositol −0.753873 4.502221 5.256094 −0.753873 3- kinase,regulatory subunit, polypeptide 1 (p85 alpha) Plekhh3 0.025038777ENSMUSG00000035172 pleckstrin −0.7507702 1.1279377 1.8787079 −0.7507702homology domain containing, family H (with MyTH4 domain) member 3 Rbm420.016107807 ENSMUSG00000036733 RNA binding −0.743897 4.178023 4.92192−0.743897 motif protein 42 Gm16287 0.029231198 ENSMUSG00000073739predicted −0.7429509 −3.0736964 −2.3307455 −0.7429509 gene 16287 Psd20.024929984 ENSMUSG00000024347 pleckstrin and −0.7429507 −1.4887338−0.7457831 −0.7429507 Sec7 domain containing 2 Cyb561d1 0.019253794ENSMUSG00000048796 cytochrome −0.7429507 3.2838557 4.0268064 −0.7429507b-561 domain containing 1 Mob2 0.022150464 ENSMUSG00000025147 MOB kinase−0.7429507 3.0348282 3.7777789 −0.7429507 activator 2 5830415F09Rik0.02634874 ENSMUSG00000028331 RIKEN cDNA −0.7429506 0.24823192 0.9911825−0.7429506 5830415F09 gene AK157302 0.03351777 ENSMUSG00000078139 cDNA−0.7418299 4.2572207 4.9990506 −0.7418299 sequence AK157302 Gm101540.026876133 ENSMUSG00000066116 predicted −0.733413 6.259459 6.992872−0.733413 gene 10154 Thap11 0.032562416 ENSMUSG00000036442 THAP domain−0.7276657 3.342468 4.0701337 −0.7276657 containing 11 Ethe1 0.027350841ENSMUSG00000064254 ethylmalonic −0.7267101 1.6704649 2.397175 −0.7267101encephalopathy 1 Rps26-ps1 0.041135248 ENSMUSG00000059775 ribosomal−0.7250665 5.626744 6.3518105 −0.7250665 protein S26, pseudogene 1Zfp523 0.021875188 ENSMUSG00000024220 zinc finger −0.7216739 1.39879162.1204655 −0.7216739 protein 523 Klhl9 0.04047058 ENSMUSG00000070923kelch-like 9 −0.7213396 4.7528524 5.474192 −0.7213396 (Drosophila)Tmem198 0.024651697 ENSMUSG00000051703 transmembrane −0.7209243−0.3512302 0.3696941 −0.7209243 protein 198 Rps8 0.04837038ENSMUSG00000047675 ribosomal −0.7206627 6.4615793 7.182242 −0.7206627protein S8 Nudt13 0.026868425 ENSMUSG00000021809 nudix −0.72038021.8617636 2.5821438 −0.7203802 (nucleoside diphosphate linked moietyX)-type motif 13 Psmb5 0.038760804 ENSMUSG00000022193 proteasome−0.720298 4.597314 5.317612 −0.720298 (prosome, macropain) subunit, betatype 5 Polr2e 0.0348101 ENSMUSG00000004667 polymerase −0.71913513.5142686 4.2334037 −0.7191351 (RNA) II (DNA directed) polypeptide EComt 0.015054342 ENSMUSG00000000326 catechol-O- −0.7187031 3.41815694.13686 −0.7187031 methyltransferase Fam100a 0.021507928ENSMUSG00000039568 family with −0.7178386 2.8186948 3.5365334 −0.7178386sequence similarity 100, member A Dusp28 0.011824952 ENSMUSG00000047067dual −0.7169556 0.2190855 0.93604106 −0.7169556 specificity phosphatase28 5730528L13Rik 0.033186235 ENSMUSG00000039693 RIKEN cDNA −0.71580441.4372658 2.1530702 −0.7158044 5730528L13 gene Fbxl6 0.036996942ENSMUSG00000022559 F-box and −0.7127183 3.9508893 4.6636076 −0.7127183leucine-rich repeat protein 6 Lrrc33 0.03724786 ENSMUSG00000052384leucine rich −0.7122502 5.7997475 6.5119977 −0.7122502 repeat containing33 Pik3ca 0.040598534 ENSMUSG00000027665 phosphatidylinositol −0.7120274.800363 5.51239 −0.712027 3- kinase, catalytic, alpha polypeptide Sppl30.04645074 ENSMUSG00000029550 signal peptide −0.7106166 5.0658555.7764716 −0.7106166 peptidase 3 Rgs1 0.017007569 ENSMUSG00000026358regulator of −0.7068314 3.6971326 4.403964 −0.7068314 G-proteinsignaling 1 Gcap14 0.025004745 ENSMUSG00000058690 granule cell −0.7063764.172332 4.878708 −0.706376 antiserum positive 14 Rabgef1 0.045662638ENSMUSG00000025340 RAB guanine −0.705021 4.49464 5.199661 −0.705021nucleotide exchange factor (GEF) 1 Vti1b 0.029425714 ENSMUSG00000021124vesicle −0.7047739 6.4313216 7.1360955 −0.7047739 transport throughinteraction with t- SNAREs 1B homolog Pter 0.029844783ENSMUSG00000026730 phosphotriesterase −0.7043781 3.2410004 3.9453785−0.7043781 related Lrmp 0.024810746 ENSMUSG00000030263 lymphoid-−0.7032047 5.2572207 5.9604254 −0.7032047 restricted membrane proteinExoc7 0.024444766 ENSMUSG00000020792 exocyst −0.7030464 3.731084.4341264 −0.7030464 complex component 7 2400003C14Rik 0.047920387ENSMUSG00000031729 RIKEN cDNA −0.7017847 5.6838603 6.385645 −0.70178472400003C14 gene Gm8112 0.040240075 ENSMUSG00000074859 predicted−0.6999323 3.3659267 4.065859 −0.6999323 gene 8112 Tjp3 0.023516202ENSMUSG00000034917 tight junction −0.6987509 0.4623566 1.1611075−0.6987509 protein 3 Park7 0.040839158 ENSMUSG00000028964 Parkinson−0.6974029 5.5694385 6.2668414 −0.6974029 disease (autosomal recessive,early onset) 7 Gm10063 0.036025446 ENSMUSG00000059333 predicted−0.6958537 4.7743006 5.4701543 −0.6958537 gene 10063 Gm6788 0.020853998ENSMUSG00000090737 predicted −0.6952334 3.1161282 3.8113616 −0.6952334gene 6788 Nmnat1 0.023781195 ENSMUSG00000028992 nicotinamide −0.69440672.0137668 2.7081735 −0.6944067 nucleotide adenylyltrans ferase 1Tbc1d10b 0.039930627 ENSMUSG00000042492 TBC1 domain −0.694137 5.5224946.216631 −0.694137 family, member 10b Parp3 0.03246012ENSMUSG00000023249 poly (ADP- −0.6925622 2.535113 3.2276752 −0.6925622ribose) polymerase family, member 3 Vps52 0.018454367 ENSMUSG00000024319vacuolar −0.6916389 4.8355966 5.5272355 −0.6916389 protein sorting 52(yeast) Rps26 0.047893744 ENSMUSG00000025362 ribosomal −0.69036055.5454235 6.235784 −0.6903605 protein S26 Immt 0.030641051ENSMUSG00000052337 inner −0.6881917 6.283416 6.9716077 −0.6881917membrane protein, mitochondrial Adap2 0.040307727 ENSMUSG00000020709ArfGAP with −0.6863671 −1.6951845 −1.0088174 −0.6863671 dual PH domains2 Vps39 0.035322167 ENSMUSG00000027291 vacuolar −0.6844366 4.99883845.683275 −0.6844366 protein sorting 39 (yeast) Fuca2 0.043429524ENSMUSG00000019810 fucosidase, −0.6837888 4.6971326 5.3809214 −0.6837888alpha-L-2, plasma Dynlrb1 0.030277705 ENSMUSG00000047459 dynein light−0.6834495 2.2337322 2.9171817 −0.6834495 chain roadblock- type 1 Mmgt20.04851589 ENSMUSG00000048497 membrane −0.681381 4.133806 4.815187−0.681381 magnesium transporter 2 Zfpl1 0.040050752 ENSMUSG00000024792zinc finger −0.6790388 3.1551225 3.8341613 −0.6790388 like protein 1Gm20457 0.036167003 ENSMUSG00000092187 predicted −0.6786962 0.648769741.3274659 −0.6786962 gene 20457 Fam82b 0.048664004 ENSMUSG00000028229family with −0.6786962 0.64876974 1.3274659 −0.6786962 sequencesimilarity 82, member B H2-Eb1 0.037901763 ENSMUSG00000060586histocompatibility −0.6778556 −1.3081615 −0.6303059 −0.6778556 2, classII antigen E beta Blvra 0.0474667 ENSMUSG00000001999 biliverdin−0.6718913 3.8475497 4.519441 −0.6718913 reductase A Srcrb4d 0.0354348ENSMUSG00000029699 scavenger −0.6675433 −0.6407369 0.02680641 −0.6675433receptor cysteine rich domain containing, group B (4 domains) Glud10.04627992 ENSMUSG00000021794 glutamate −0.6664464 6.44082 7.1072664−0.6664464 dehydrogenase 1 Fdx1l 0.04709346 ENSMUSG00000079677ferredoxin 1- −0.6660187 4.133806 4.7998247 −0.6660187 like2610318N02Rik 0.027701477 ENSMUSG00000049916 RIKEN cDNA −0.66463841.2042885 1.8689269 −0.6646384 2610318N02 gene Cbara1 0.025856437ENSMUSG00000020111 calcium −0.6626866 4.2838554 4.946542 −0.6626866binding atopy-related autoantigen 1 AI837181 0.037062764ENSMUSG00000047423 expressed −0.6597565 2.7842848 3.4440413 −0.6597565sequence AI837181 Agk 0.028081048 ENSMUSG00000029916 acylglycerol−0.6595563 2.813829 3.4733853 −0.6595563 kinase Slc44a2 0.027341165ENSMUSG00000057193 solute carrier −0.6587429 3.1627963 3.8215392−0.6587429 family 44, member 2 Atp6v0d1 0.02142147 ENSMUSG00000013160ATPase, H+ −0.6567502 6.2455244 6.9022746 −0.6567502 transporting,lysosomal V0 subunit D1 Adat3 0.0407096 ENSMUSG00000035370 adenosine−0.6546907 1.2337323 1.888423 −0.6546907 deaminase, tRNA-specific 3,TAD2 homolog (S. cerevisiae) Dlx4 0.029477518 ENSMUSG00000020871distal-less −0.6498416 −4.3956246 −3.745783 −0.6498416 homeobox 4 Fzd90.030664086 ENSMUSG00000049551 frizzled −0.6498416 −4.3956246 −3.745783−0.6498416 homolog 9 (Drosophila) Gm13031 0.03036407 ENSMUSG00000087698predicted −0.6498414 −3.3956244 −2.745783 −0.6498414 gene 13031 Jag20.041047707 ENSMUSG00000002799 jagged 2 −0.6498413 −2.0736964 −1.4238551−0.6498413 Gm5665 0.048196785 ENSMUSG00000074863 predicted −0.6498413−2.8106618 −2.1608205 −0.6498413 gene 5665 Cdk18 0.035990108ENSMUSG00000026437 cyclin- −0.6487923 5.4451537 6.093946 −0.6487923dependent kinase 18 Wsb2 0.048568413 ENSMUSG00000029364 WD repeat−0.6455825 5.747759 6.3933415 −0.6455825 and SOCS box- containing 2Rpl14 0.04038221 ENSMUSG00000025794 ribosomal −0.645187 6.155603 6.80079−0.645187 protein L14 Gm11457 0.044966727 ENSMUSG00000086453 predicted−0.6448752 1.2042885 1.8491637 −0.6448752 gene 11457 Adck5 0.025202971ENSMUSG00000022550 aarF domain −0.6416361 3.6514995 4.2931356 −0.6416361containing kinase 5 Tmub2 0.04888207 ENSMUSG00000034757 transmembrane−0.6409414 2.6865246 3.327466 −0.6409414 and ubiquitin-like domaincontaining 2 Atp5l-ps1 0.033605512 ENSMUSG00000072460 ATP synthase,−0.6403808 3.2768009 3.9171817 −0.6403808 H+ transporting, mitochondrialF0 complex, subunit g, pseudogene 1 Rgs16 0.04644141 ENSMUSG00000026475regulator of −0.639681 4.759194 5.398875 −0.639681 G-protein signaling16 Rpl21- 0.04064617 ENSMUSG00000062152 ribosomal −0.6384003 3.32547473.963875 −0.6384003 ps14 protein L21, pseudogene 14 Snx11 0.046817992ENSMUSG00000020876 sorting nexin −0.634604 3.0514588 3.6860628 −0.63460411 Nln 0.048038434 ENSMUSG00000021710 neurolysin −0.6335058 4.53659065.1700964 −0.6335058 (metallopeptidase M3 family) Acss2 0.039891824ENSMUSG00000027605 acyl-CoA −0.6298728 3.2042885 3.8341613 −0.6298728synthetase short-chain family member 2 Gm16744 0.04230707ENSMUSG00000086002 predicted −0.6287797 −0.8720624 −0.2432828 −0.6287797gene, 16744 1110051M20Rik 0.042616416 ENSMUSG00000040591 RIKEN cDNA−0.627511 4.2536316 4.8811426 −0.627511 1110051M20 gene Rab1b0.042926516 ENSMUSG00000024870 RAB1B, −0.6267397 5.902438 6.5291777−0.6267397 member RAS oncogene family Ndufs5 0.027461376ENSMUSG00000028648 NADH −0.6264772 1.979415 2.6058922 −0.6264772dehydrogenase (ubiquinone) Fe—S protein 5 Tmem42 0.034604322ENSMUSG00000066233 transmembrane −0.6259945 1.535113 2.1611075−0.6259945 protein 42 Mapkapk2 0.03941688 ENSMUSG00000016528 MAP kinase-−0.6252842 6.7155113 7.3407955 −0.6252842 activated protein kinase 2Stambpl1 0.035237126 ENSMUSG00000024776 STAM binding −0.62507825.4197593 6.0448375 −0.6250782 protein like 1 Pgam2 0.039034486ENSMUSG00000020475 phosphoglycerate −0.6243063 −1.1476969 −0.5233907−0.6243063 mutase 2 Fam160b1 0.04417353 ENSMUSG00000033478 family with−0.6238462 3.7336588 4.357505 −0.6238462 sequence similarity 160, memberB1 Ttll12 0.048118092 ENSMUSG00000016757 tubulin −0.6235144 4.53659065.160105 −0.6235144 tyrosine ligase-like family, member 12 Nudt150.033909168 ENSMUSG00000033405 nudix −0.6220963 1.7336587 2.355755−0.6220963 (nucleoside diphosphate linked moiety X)-type motif 15 Tram20.049381044 ENSMUSG00000041779 translocating −0.6220071 1.89899642.5210035 −0.6220071 chain- associating membrane protein 2 Ociad20.0425186 ENSMUSG00000029153 OCIA domain −0.6212722 −1.3081615−0.6868893 −0.6212722 containing 2 Bloc1s3 0.04529189 ENSMUSG00000057667biogenesis of −0.620094 2.2190855 2.8391795 −0.620094 lysosome- relatedorganelles complex-1, subunit 3 Rassf1 0.037896954 ENSMUSG00000010067Ras −0.6198733 3.4309242 4.0507975 −0.6198733 association (RalGDS/AF- 6)domain family member 1 Sntb2 0.038723968 ENSMUSG00000041308 syntrophin,−0.619171 4.99991 5.619081 −0.619171 basic 2 Kcnab2 0.037089523ENSMUSG00000028931 potassium −0.6191615 4.422958 5.0421195 −0.6191615voltage-gated channel, shaker- related subfamily, beta member 2 Rragc0.04885698 ENSMUSG00000028646 Ras-related −0.6159734 6.085671 6.7016444−0.6159734 GTP binding C Irf3 0.038443018 ENSMUSG00000003184 interferon−0.615951 3.2554274 3.8713784 −0.615951 regulatory factor 33110043O21Rik 0.046679143 ENSMUSG00000028300 RIKEN cDNA −0.61401545.588082 6.2020974 −0.6140154 3110043O21 gene Tnfaip8 0.036621507ENSMUSG00000062210 tumor −0.613772 4.529188 5.14296 −0.613772 necrosisfactor, alpha- induced protein 8 Dscr3 0.034768607 ENSMUSG00000022898Down −0.6132714 4.3169026 4.930174 −0.6132714 syndrome critical regiongene 3 Ppp1r16a 0.034497265 ENSMUSG00000033819 protein −0.61294173.6487699 4.2617116 −0.6129417 phosphatase 1, regulatory (inhibitor)subunit 16A Rpl17-ps3 0.041614436 ENSMUSG00000069392 ribosomal −0.6092396.650135 7.259374 −0.609239 protein L17, pseudogene 3 5430403G16Rik0.04923931 ENSMUSG00000072763 RIKEN cDNA −0.6085005 0.4870187 1.0955192−0.6085005 5430403G16 gene Mpst 0.04476959 ENSMUSG00000071711mercaptopyruvate −0.6077339 2.2264276 2.8341615 −0.6077339sulfurtransferase Rab14 0.04740811 ENSMUSG00000026878 RAB14, −0.60710366.0426474 6.649751 −0.6071036 member RAS oncogene family Rtkn 0.04634605ENSMUSG00000034930 rhotekin −0.6054473 −1.9361928 −1.3307455 −0.6054473Gm11788 0.048462883 ENSMUSG00000086929 predicted −0.6054473 −1.9361928−1.3307455 −0.6054473 gene 11788 BC024978 0.045672644 ENSMUSG00000078786cDNA −0.605103 2.6377988 3.2429018 −0.605103 sequence BC024978 Tmem86b0.042776905 ENSMUSG00000045282 transmembrane −0.603745 0.33229610.93604106 −0.603745 protein 86B 2510039O18Rik 0.03078932ENSMUSG00000044496 RIKEN cDNA −0.601857 5.210781 5.812638 −0.6018572510039O18 gene Ankmy2 0.038953494 ENSMUSG00000036188 ankyrin −0.60184722.9531038 3.554951 −0.6018472 repeat and MYND domain containing 2Txndc11 0.026081089 ENSMUSG00000022498 thioredoxin −0.6013887 4.5395415.1409297 −0.6013887 domain containing 11 Nhp2 0.047920577ENSMUSG00000001056 NHP2 −0.601229 4.57879 5.180019 −0.601229ribonucleoprotein homolog (yeast) Oxa1l 0.044693552 ENSMUSG00000000959oxidase −0.6010437 4.9848366 5.5858803 −0.6010437 assembly 1- like Plcb30.040368132 ENSMUSG00000024960 phospholipase −0.5995494 4.09622864.695778 −0.5995494 C, beta 3 Mylip 0.040585697 ENSMUSG00000038175myosin −0.5987937 2.9531038 3.5518975 −0.5987937 regulatory light chaininteracting protein Psmd5 0.047061477 ENSMUSG00000026869 proteasome−0.5970666 5.0473194 5.644386 −0.5970666 (prosome, macropain) 26Ssubunit, non-ATPase, 5 Gss 0.049137637 ENSMUSG00000027610 glutathione−0.5966295 4.0922155 4.688845 −0.5966295 synthetase Grin1 0.04237296ENSMUSG00000026959 glutamate −0.5953935 −2.2256994 −1.6303059 −0.5953935receptor, ionotropic, NMDA1 (zeta 1) Rpl17 0.000773 ENSMUSG00000062328ribosomal −0.5925903 6.0826397 6.67523 −0.5925903 protein L17 Rab5b0.041810345 ENSMUSG00000000711 RAB5B, −0.5925451 4.6446652 5.2372103−0.5925451 member RAS oncogene family Kat2b 0.048757337ENSMUSG00000000708 K(lysine) −0.5910521 3.1893382 3.7803903 −0.5910521acetyltransferase 2B Rrbp1 0.04895402 ENSMUSG00000027422 ribosome−0.5907982 6.131364 6.7221622 −0.5907982 binding protein 1 Serpinb9b0.046480495 ENSMUSG00000021403 serine (or −0.5884407 −1.3956243−0.8071836 −0.5884407 cysteine) peptidase inhibitor, clade B, member 9bBC030307 0.045264874 ENSMUSG00000044937 cDNA −0.5857109 0.127937660.7136486 −0.5857109 sequence BC030307 Pcyt2 0.04845 ENSMUSG00000025137phosphate −0.585105 4.362599 4.947704 −0.585105 cytidylyltransferase 2,ethanolamine Map2k7 0.047179256 ENSMUSG00000002948 mitogen- −0.40151065.2838554 5.685366 −0.4015106 activated protein kinase kinase 7 Fbxo330.044220295 ENSMUSG00000035329 F-box protein 1.066019 5.693826 4.6278071.066019 33 Adam15 0.049121536 ENSMUSG00000028041 a disintegrin1.1044345 6.393909 5.2894745 1.1044345 and metallopeptidase domain 15(metargidin) Slc25a33 0.04958606 ENSMUSG00000028982 solute carrier1.1154347 4.7272034 3.6117687 1.1154347 family 25, member 33 Lilrb40.044434078 ENSMUSG00000062593 leukocyte 1.1315183 5.5951886 4.46367031.1315183 immunoglobulin- like receptor, subfamily B, member 4 Phgdh0.043934878 ENSMUSG00000053398 3- 1.1419146 8.229285 7.0873704 1.1419146phosphoglycerate dehydrogenase Itgam 0.04708623 ENSMUSG00000030786integrin alpha M 1.1575141 6.4313216 5.2738075 1.1575141 Papd70.045507006 ENSMUSG00000034575 PAP 1.1577465 5.6149035 4.4571571.1577465 associated domain containing 7 Slc2a3 0.048934277ENSMUSG00000003153 solute carrier 1.1751518 4.8415856 3.66643381.1751518 family 2 (facilitated glucose transporter), member 3 Rin20.043170445 ENSMUSG00000001768 Ras and Rab 1.2039381 4.8331943 3.62925621.2039381 interactor 2 Sorl1 0.038947 ENSMUSG00000049313 sortilin-1.2207785 5.069942 3.8491635 1.2207785 related receptor, LDLR class Arepeats- containing Tlr2 0.043592107 ENSMUSG00000027995 toll-like1.225015 6.882244 5.657229 1.225015 receptor 2 Mycn 0.040442508ENSMUSG00000037169 v-myc 1.2253772 7.345843 6.1204658 1.2253772myelocytomatosis viral related oncogene, neuroblastom a derived (avian)Ifi203 0.0450752 ENSMUSG00000039997 interferon 1.2263527 5.39146234.1651096 1.2263527 activated gene 203 Psph 0.047209337ENSMUSG00000029446 phosphoserine 1.2327685 5.4157505 4.182982 1.2327685phosphatase Tcof1 0.044333804 ENSMUSG00000024613 Treacher 1.24563696.1352696 4.8896327 1.2456369 Collins Franceschetti syndrome 1, homologAdar 0.03601896 ENSMUSG00000027951 adenosine 1.266367 6.79049 5.5241231.266367 deaminase, RNA-specific Ogfr 0.02613318 ENSMUSG00000049401opioid growth 1.2672534 5.8403897 4.5731363 1.2672534 factor receptorNfkbid 0.030824393 ENSMUSG00000036931 nuclear factor 1.2704837 5.56727174.296788 1.2704837 of kappa light polypeptide gene enhancer in B-cellsinhibitor, delta Gm6736 0.024999972 ENSMUSG00000071414 predicted1.2907186 8.271154 6.9804354 1.2907186 gene 6736 Fads2 0.026953876ENSMUSG00000024665 fatty acid 1.3091817 5.6204877 4.311306 1.3091817desaturase 2 E330016A19Rik 0.042681493 ENSMUSG00000032344 RIKEN cDNA1.3128021 4.629515 3.3167129 1.3128021 E330016A19 gene Bcat1 0.039503414ENSMUSG00000030268 branched 1.3130115 7.048355 5.7353435 1.3130115 chainaminotransferase 1, cytosolic Sh3bp5 0.02677949 ENSMUSG00000021892SH3-domain 1.3191829 4.8307877 3.5116048 1.3191829 binding protein 5(BTK- associated) Ncf1 0.033802066 ENSMUSG00000015950 neutrophil1.3297525 6.17518 4.8454275 1.3297525 cytosolic factor 1 Clec5a0.03368596 ENSMUSG00000029915 C-type lectin 1.3339666 5.980501 4.64653441.3339666 domain family 5, member a Tnip3 0.046092596 ENSMUSG00000044162TNFAIP3 1.35819 5.035873 3.677683 1.35819 interacting protein 3 Fam129a0.038229138 ENSMUSG00000026483 family with 1.358445 4.789251 3.4308061.358445 sequence similarity 129, member A 4731419I09Rik 0.031881414ENSMUSG00000091513 RIKEN cDNA 1.3631143 5.4396367 4.0765224 1.36311434731419I09 gene Stom 0.028415862 ENSMUSG00000026880 stomatin 1.3868175.465462 4.078645 1.386817 Adam17 0.012626361 ENSMUSG00000052593 adisintegrin 1.3891568 6.7518983 5.3627415 1.3891568 and metallopeptidasedomain 17 Psat1 0.047628995 ENSMUSG00000024640 phosphoserine 1.4010878.7339 7.332813 1.401087 aminotransferase 1 Zw10 0.020814842ENSMUSG00000032264 ZW10 1.423672 5.65898 4.235308 1.423672 homolog(Drosophila), centromere/kinetochore protein Ripk2 0.035168238ENSMUSG00000041135 receptor 1.427343 4.539541 3.112198 1.427343(TNFRSF)- interacting serine- threonine kinase 2 Pcyox1l 0.027063185ENSMUSG00000024579 prenylcysteine 1.4283414 3.8186948 2.39035341.4283414 oxidase 1 like Rbpsuhrs3 0.018088786 ENSMUSG00000079575recombining 1.4293184 6.848442 5.4191236 1.4293184 binding proteinsuppressor of hairless (Drosophila), related sequence 3 Cd74 0.0275401ENSMUSG00000024610 CD74 antigen 1.4491129 7.1620784 5.7129655 1.4491129(invariant polypeptide of major histocompatibility complex, class IIantigen- associated) Clec4e 0.03084233 ENSMUSG00000030142 C-type lectin1.4540292 3.8781712 2.424142 1.4540292 domain family 4, member e Sash10.020445129 ENSMUSG00000015305 SAM and SH3 1.4577389 4.98808 3.53034111.4577389 domain containing 1 Parp12 0.016752578 ENSMUSG00000038507 poly(ADP- 1.4689444 6.2917514 4.822807 1.4689444 ribose) polymerase family,member 12 Daam1 0.014327282 ENSMUSG00000034574 dishevelled 1.46924315.6343527 4.1651096 1.4692431 associated activator of morphogenesis 1Gm15645 0.04660924 ENSMUSG00000086414 predicted 1.4707485 5.3322963.8615475 1.4707485 gene 15645 Mt2 0.021577373 ENSMUSG00000031762metallothionein 2 1.4811826 3.8851466 2.403964 1.4811826 Slfn40.020475224 ENSMUSG00000000204 schlafen 4 1.4817953 6.2803326 4.79853731.4817953 Rbpj 0.036361992 ENSMUSG00000039191 recombination 1.49033957.8968415 6.406502 1.4903395 signal binding protein for immunoglobulinkappa J region Ptplb 0.019518027 ENSMUSG00000035376 protein 1.49233864.991316 3.4989774 1.4923386 tyrosine phosphatase- like (proline insteadof catalytic arginine), member b Asph 0.026277151 ENSMUSG00000028207aspartate- 1.4966014 7.1630354 5.666434 1.4966014 beta- hydroxylaseSpata13 0.01995978 ENSMUSG00000021990 spermatogenesis 1.500841 5.0709623.570121 1.500841 associated 13 Gp49a 0.01797235 ENSMUSG00000089672glycoprotein 1.52455 5.52696 4.00241 1.52455 49 A Glrx 0.020311931ENSMUSG00000021591 glutaredoxin 1.5271039 3.8758385 2.3487346 1.5271039Slc6a4 0.015190769 ENSMUSG00000020838 solute carrier 1.5354503 6.45025734.914807 1.5354503 family 6 (neurotransmitter transporter, serotonin),member 4 Setdb2 0.023574898 ENSMUSG00000071350 SET domain, 1.53762444.5600257 3.0224013 1.5376244 bifurcated 2 Eif2ak2 0.00837484ENSMUSG00000024079 eukaryotic 1.551614 6.850225 5.298611 1.551614translation initiation factor 2-alpha kinase 2 Stat2 0.022812009ENSMUSG00000040033 signal 1.5807465 4.598729 3.0179825 1.5807465transducer and activator of transcription 2 Herpud1 0.009253571ENSMUSG00000031770 homocysteine- 1.58482 5.684527 4.099707 1.58482inducible, endoplasmic reticulum stress- inducible, ubiquitin-likedomain member 1 Tmem2 0.01044533 ENSMUSG00000024754 transmembrane1.585879 6.534744 4.948865 1.585879 protein 2 Bmf 0.03913493ENSMUSG00000040093 BCL2 1.6214382 4.1298966 2.5084584 1.6214382modifying factor Mitd1 0.020194989 ENSMUSG00000026088 MIT, 1.62761224.689184 3.0615718 1.6276122 microtubule interacting and transport,domain containing 1 Slfn3 0.017630316 ENSMUSG00000018986 schlafen 31.6345547 4.6744967 3.039942 1.6345547 Tasp1 0.017170591ENSMUSG00000039033 taspase, 1.6429404 4.678517 3.0355766 1.6429404threonine aspartase 1 Ifi35 0.013708029 ENSMUSG00000010358 interferon-1.6526694 3.8688183 2.2161489 1.6526694 induced protein 35 Slc11a10.002501 ENSMUSG00000026177 solute carrier 1.6735306 5.9848366 4.3113061.6735306 family 11 (proton- coupled divalent metal ion transporters),member 1 Ssh2 0.012622531 ENSMUSG00000037926 slingshot 1.691286 5.6528623.961576 1.691286 homolog 2 (Drosophila) Parp10 0.015827406ENSMUSG00000063268 poly (ADP- 1.6941132 4.7076635 3.0135503 1.6941132ribose) polymerase family, member 10 Uba7 0.016567297 ENSMUSG00000032596ubiquitin-like 1.7041156 4.98808 3.2839644 1.7041156 modifier activatingenzyme 7 Fam49a 0.014623731 ENSMUSG00000020589 family with 1.71165494.9956193 3.2839644 1.7116549 sequence similarity 49, member A Dennd2d0.031796068 ENSMUSG00000027901 DENN/MADD 1.7250655 4.427743 2.70267751.7250655 domain containing 2D Pld4 0.015250916 ENSMUSG00000052160phospholipase 1.7269177 5.590929 3.8640113 1.7269177 D family, member 4Fosl1 0.03473085 ENSMUSG00000024912 fos-like 1.7354727 3.28737021.5518975 1.7354727 antigen 1 Ugcg 0.015557361 ENSMUSG00000028381UDP-glucose 1.7373785 4.746483 3.0091045 1.7373785 ceramideglucosyltransferase Slc7a5 0.014336524 ENSMUSG00000040010 solute carrier1.7564154 7.282095 5.5256796 1.7564154 family 7 (cationic amino acidtransporter, y+ system), member 5 Odc1 0.003826073 ENSMUSG00000011179ornithine 1.7847224 8.635129 6.8504066 1.7847224 decarboxylase,structural 1 Gch1 0.032283947 ENSMUSG00000037580 GTP 1.7982392 3.32547471.5272355 1.7982392 cyclohydrolase 1 Slc6a9 0.012537855ENSMUSG00000028542 solute carrier 1.8009172 4.5629287 2.76201151.8009172 family 6 (neurotransmitter transporter, glycine), member 9Phf15 0.006952753 ENSMUSG00000020387 PHD finger 1.803466 6.1818044.378338 1.803466 protein 15 Gpr179 0.027233575 ENSMUSG00000070337 Gprotein- 1.812993 3.749034 1.936041 1.812993 coupled receptor 179 Sp1100.008639846 ENSMUSG00000070034 Sp110 1.8445542 4.076051 2.23149681.8445542 nuclear body protein Tpst1 0.032691307 ENSMUSG00000034118protein- 1.8491342 4.3575926 2.5084584 1.8491342 tyrosinesulfotransferase 1 Qsox1 0.007972689 ENSMUSG00000033684 quiescin Q61.8776744 4.7805486 2.9028742 1.8776744 sulfhydryl oxidase 1 Ier30.014196688 ENSMUSG00000003541 immediate 1.890267 4.981586 3.0913191.890267 early response 3 Ets2 0.006089266 ENSMUSG00000022895 E26 avian1.8925752 5.7541227 3.8615475 1.8925752 leukemia oncogene 2, 3′ domainZc3h12c 0.004831877 ENSMUSG00000035164 zinc finger 1.8958522 6.2268854.3310328 1.8958522 CCCH type containing 12C Ccdc24 0.030835103ENSMUSG00000078588 coiled-coil 1.8994296 3.6239665 1.7245369 1.8994296domain containing 24 Plk2 0.008188616 ENSMUSG00000021701 polo-like1.9049172 5.0740175 3.1691003 1.9049172 kinase 2 (Drosophila) Stat10.007773834 ENSMUSG00000026104 signal 1.9285366 5.6984534 3.76991681.9285366 transducer and activator of transcription 1 Chac1 0.031882036ENSMUSG00000027313 ChaC, cation 1.9297678 3.6758378 1.74607 1.9297678transport regulator-like 1 (E. coli) Gng2 0.035535995 ENSMUSG00000043004guanine 1.9435497 3.6128042 1.6692545 1.9435497 nucleotide bindingprotein (G protein), gamma 2 Grap 0.003583301 ENSMUSG00000004837GRB2-related 1.9460665 6.5101385 4.564072 1.9460665 adaptor proteinPycr1 0.025833854 ENSMUSG00000025140 pyrroline-5- 1.95558527 2.75412270.79853743 1.95558527 carboxylate reductase 1 Trim12c 0.012106774ENSMUSG00000057143 tripartite 1.9593374 4.2135544 2.254217 1.9593374motif- containing 12C Clec4d 0.007304858 ENSMUSG00000030144 C-typelectin 1.9701681 4.1551223 2.1849542 1.9701681 domain family 4, member dCpd 0.002164662 ENSMUSG00000020841 carboxypeptidase D 1.990618 8.7978246.807206 1.990618 Dtx3l 0.002565308 ENSMUSG00000049502 deltex 3-like2.010299 5.4739695 3.4636705 2.010299 (Drosophila) Car12 0.015473221ENSMUSG00000032373 carbonic 2.0304694 4.0306406 2.0001712 2.0304694anyhydrase 12 Lrrc17 0.006864152 ENSMUSG00000039883 leucine rich2.038969 5.394724 3.355755 2.038969 repeat containing 17 Gm175490.002010584 ENSMUSG00000091543 predicted 2.0470712 5.278568 3.23149682.0470712 gene, 17549 Fyb 0.001659938 ENSMUSG00000022148 FYN binding2.0631156 6.3173323 4.2542167 2.0631156 protein Ccl3 0.003072253ENSMUSG00000000982 chemokine 2.0781493 7.3361187 5.2579694 2.0781493(C-C motif) ligand 3 Trim5 0.028752334 ENSMUSG00000060441 tripartite2.0891548 2.9081564 0.8190016 2.0891548 motif- containing 5 Dusp20.001119755 ENSMUSG00000027368 dual 2.097596 6.005255 3.907659 2.097596specificity phosphatase 2 Lyz1 0.001480785 ENSMUSG00000069515 lysozyme 12.1054833 5.294374 3.1888907 2.1054833 Dhrs3 0.002936547ENSMUSG00000066026 dehydrogenase/ 2.1068875 4.804048 2.6971605 2.1068875reductase (SDR family) member 3 Slc1a4 0.00929272 ENSMUSG00000020142solute carrier 2.1085265 4.301343 2.1928165 2.1085265 family 1(glutamate/neutral amino acid transporter), member 4 Epsti1 0.044788834ENSMUSG00000022014 epithelial 2.11605915 2.6432946 0.52723545 2.11605915stromal interaction 1 (breast) H2-T24 0.001531115 ENSMUSG00000053835histocompatibility 2.1219106 5.3534074 3.2314968 2.1219106 2, T regionlocus 24 Zc3h12a 0.001478526 ENSMUSG00000042677 zinc finger 2.12274814.1318526 2.0091045 2.1227481 CCCH type containing 12A Sass6 0.001012042ENSMUSG00000027959 spindle 2.123662 6.059703 3.936041 2.123662 assembly6 homolog (C. elegans) Abcc4 0.007724259 ENSMUSG00000032849 ATP-binding2.1336435 5.597314 3.4636705 2.1336435 cassette, sub- family C(CFTR/MRP), member 4 Mef2c 0.000477217 ENSMUSG00000005583 myocyte2.1434676 6.121061 3.9775934 2.1434676 enhancer factor 2C Mpeg10.000799983 ENSMUSG00000046805 macrophage 2.1497637 6.5332637 4.38352.1497637 expressed gene 1 Rnf213 0.007161953 ENSMUSG00000070327 ringfinger 2.15004 10.065887 7.915847 2.15004 protein 213 Dusp5 0.009104466ENSMUSG00000034765 dual 2.1525025 3.5082576 1.3557551 2.1525025specificity phosphatase 5 Irf9 0.008142755 ENSMUSG00000002325 interferon2.1531142 5.075034 2.9219198 2.1531142 regulatory factor 9 Tlr90.007655328 ENSMUSG00000045322 toll-like 2.1671071 4.3441563 2.17704922.1671071 receptor 9 Rapgef5 0.018954162 ENSMUSG00000041992 Rap guanine2.177482 3.789251 1.611769 2.177482 nucleotide exchange factor (GEF) 5Akap5 0.001063172 ENSMUSG000000021057 A kinase 2.202505 5.3022123.099707 2.202505 (PRKA) anchor protein 5 Serpine1 0.005375954ENSMUSG000000037411 serine (or 2.204582 5.140623 2.936041 2.204582cysteine) peptidase inhibitor, clade E, member 1 Xylt2 0.003379382ENSMUSG000000020868 xylosyltransferase 2.2256849 5.0190606 2.79337572.2256849 II Sash3 0.000824317 ENSMUSG000000031101 SAM and SH3 2.24359476.8015924 4.5579977 2.2435947 domain containing 3 B4galt6 0.0185172ENSMUSG000000056124 UDP- 2.2701052 3.7207193 1.4506141 2.2701052Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 6 Herc60.012329049 ENSMUSG000000029798 hect domain 2.2897381 3.543955 1.25421692.2897381 and RLD 6 Lgals3bp 0.001605042 ENSMUSG000000033880 lectin,2.3190542 5.550551 3.2314968 2.3190542 galactoside- binding, soluble, 3binding protein Slfn5 0.001191921 ENSMUSG000000054404 schlafen 52.3321457 5.6738253 3.3416796 2.3321457 Cd52 0.035810307ENSMUSG000000000682 CD52 antigen 2.3386994 3.3117347 0.9730353 2.3386994Ggta1 0.019090641 ENSMUSG000000035778 glycoprotein 2.3622925 3.82596281.4636703 2.3622925 galactosyltransferase alpha 1, 3 Tlr7 0.02658981ENSMUSG000000044583 toll-like 2.37990606 2.804048 0.42414194 2.37990606receptor 7 Fli1 0.007515412 ENSMUSG000000016087 Friend 2.38039273.9685104 1.5881177 2.3803927 leukemia integration 1 Oasl1 0.000525786ENSMUSG000000041827 2′-5′ 2.3906102 7.1178565 4.7272463 2.3906102oligoadenylate synthetase- like 1 Mndal 0.004260393 ENSMUSG000000090272myeloid 2.3974011 4.5902176 2.1928165 2.3974011 nuclear differentiationantigen like Gas7 0.000438789 ENSMUSG000000033066 growth arrest2.4181176 7.49464 5.0765224 2.4181176 specific 7 Stab1 0.031446114ENSMUSG000000042286 stabilin 1 2.4637601 3.342468 0.8787079 2.4637601Lck 0.008432007 ENSMUSG000000000409 lymphocyte 2.47206192 2.94867130.47660938 2.47206192 protein tyrosine kinase Pdcd1 0.024454752ENSMUSG000000026285 programmed 2.47214922 2.813829 0.34167978 2.47214922cell death 1 Otub2 0.03326988 ENSMUSG000000021203 OTU domain, 2.474283.1435344 0.6692544 2.47428 ubiquitin aldehyde binding 2 Tanc20.03190521 ENSMUSG000000053580 tetratricopeptide 2.50528675 2.7892510.28396425 2.50528675 repeat, ankyrin repeat and coiled-coil containing2 Gm7676 0.042453267 ENSMUSG000000068631 predicted 2.54145726 3.27680090.73534364 2.54145726 gene 7676 Cp 0.039974507 ENSMUSG000000003617ceruloplasmin 2.5422796 2.6377988 0.0955192 2.5422796 Pck2 0.000345685ENSMUSG000000040618 phosphoenol 2.5555408 5.9458942 3.3903534 2.5555408pyruvate carboxykinase 2 (mitochondrial) Lyl1 0.011417538ENSMUSG00000034041 lymphoblastomic 2.5561529 3.5291882 0.97303532.5561529 leukemia 1 BC006779 0.000513289 ENSMUSG00000027580 cDNA2.5614315 6.8995705 4.338139 2.5614315 sequence BC006779 Dab2 0.0005445ENSMUSG00000022150 disabled 2.5665724 5.390645 2.8240726 2.5665724homolog 2 (Drosophila) Cd36 0.000197919 ENSMUSG00000002944 CD36 antigen2.5687684 7.523425 4.9546566 2.5687684 Gm885 0.000151064ENSMUSG00000040528 predicted 2.5931254 4.3709044 1.777779 2.5931254 gene885 Cxcl16 0.040038653 ENSMUSG00000018920 chemokine 2.617381 2.71290020.0955192 2.617381 (C—X—C motif) ligand 16 Samd9l 0.001224701ENSMUSG00000047735 sterile alpha 2.6175766 5.347527 2.7299504 2.6175766motif domain containing 9- like Ifitm3 0.000167685 ENSMUSG00000025492interferon 2.6401358 7.2650404 4.6249046 2.6401358 induced transmembraneprotein 3 Tlr1 0.000515847 ENSMUSG00000044827 toll-like 2.644155 4.999912.355755 2.644155 receptor 1 Icosl 0.0499492 ENSMUSG00000000732 icosligand 2.6630416 0.3322961 −2.3307455 2.6630416 5730469M10Rik0.008745185 ENSMUSG00000021792 RIKEN cDNA 2.6663043 3.979415 1.31311072.6663043 5730469M10 gene Oas1a 5.18934E−06 ENSMUSG00000052776 2′-5′2.6766694 6.7122464 4.035577 2.6766694 oligoadenylate synthetase 1APrss16 0.029725667 ENSMUSG00000006179 protease, 2.73307769 2.86176370.12868601 2.73307769 serine, 16 (thymus) Pla2g5 0.044189025ENSMUSG00000041193 phospholipase 2.73704227 2.6542242 −0.08281812.73704227 A2, group V Pros1 0.044148285 ENSMUSG00000022912 protein S2.74788957 2.6650715 −0.0828181 2.74788957 (alpha) Gm4902 0.038773473ENSMUSG00000091649 predicted 2.75766276 2.1818047 −0.5758581 2.75766276gene 4902 Ptgs2 0.000652096 ENSMUSG00000032487 prostaglandin- 2.78818894.6071906 1.8190017 2.7881889 endoperoxide synthase 2 D330045A20Rik0.03840468 ENSMUSG00000042498 RIKEN cDNA 2.82533312 2.3525686 −0.47276452.82533312 D330045A20 gene Gbp7 0.001749768 ENSMUSG00000040253 guanylate2.8321975 4.384095 1.5518975 2.8321975 binding protein 7 Abcc30.04643164 ENSMUSG00000020865 ATP-binding 2.83324138 2.54689 −0.28635142.83324138 cassette, sub- family C (CFTR/MRP), member 3 Lsp1 0.006437104ENSMUSG00000018819 lymphocyte 2.8433657 3.6623673 0.8190016 2.8433657specific 1 Fads6 0.03632363 ENSMUSG00000044788 fatty acid 2.855686752.3322961 −0.5233907 2.85568675 desaturase domain family, member 6 Dlg40.015582533 ENSMUSG00000020886 discs, large 2.8627704 2.0555868−0.8071836 2.8627704 homolog 4 (Drosophila) Spire2 0.04822587ENSMUSG00000010154 spire 2.86800703 0.99669313 −1.8713139 2.86800703homolog 2 (Drosophila) Parp9 3.87374E−05 ENSMUSG00000022906 poly (ADP-2.8685094 5.217244 2.3487346 2.8685094 ribose) polymerase family, member9 Spred3 0.020723633 ENSMUSG00000037239 sprouty- 2.8737209 2.1279378−0.7457831 2.8737209 related, EVH1 domain containing 3 Oas1c 0.04526947ENSMUSG00000001166 2′-5′ 2.8841373 1.7233167 −1.1608206 2.8841373oligoadenylate synthetase 1C Procr 0.029140951 ENSMUSG00000027611protein C 2.886866 1.804048 −1.082818 2.886866 receptor, endothelialPlek 0.000116704 ENSMUSG00000020120 pleckstrin 2.9145183 7.86338334.948865 2.9145183 Soat2 0.04084924 ENSMUSG00000023045 sterol O-2.91756277 2.5410135 −0.3765493 2.91756277 acyltransferase 2 Bst20.000290517 ENSMUSG00000046718 bone marrow 2.9644963 5.522494 2.55799772.9644963 stromal cell antigen 2 Oas1g 4.99617E−06 ENSMUSG000000668612′-5′ 2.9733734 6.706023 3.7326496 2.9733734 oligoadenylate synthetase1G Acsbg1 0.011451526 ENSMUSG00000032281 acyl-CoA 2.97743206 3.62396650.64653444 2.97743206 synthetase bubblegum family member 1 Srgn0.000519223 ENSMUSG00000020077 serglycin 2.9888318 4.8379955 1.84916372.9888318 Cd300lf 0.048743 ENSMUSG00000047798 CD300 2.994014760.83319426 −2.1608205 2.99401476 antigen like family member F Btg20.013627362 ENSMUSG00000020423 B-cell 3.04782124 3.0390038 −0.00881743.04782124 translocation gene 2, anti- proliferative Lyz2 0.000114821ENSMUSG00000069516 lysozyme 2 3.0592905 8.7250185 5.665728 3.0592905Tmem176a 0.001501859 ENSMUSG00000023367 transmembrane 3.07977944.3339963 1.2542169 3.0797794 protein 176A Cd300ld 0.006088423ENSMUSG00000034641 CD300 3.08196247 3.1435344 0.06157193 3.08196247molecule-like family member d Ikbke 0.011466974 ENSMUSG00000042349inhibitor of 3.0988679 3.468562 0.3696941 3.0988679 kappaB kinaseepsilon Sepw1 0.021194948 ENSMUSG00000041571 selenoprotein 3.105046452.8617637 −0.2432828 3.10504645 W, muscle 1 Hap1 0.006396474ENSMUSG00000006930 huntingtin- 3.10895079 3.1357572 0.026806413.10895079 associated protein 1 Trim34a 0.03032563 ENSMUSG00000056144tripartite 3.10989568 2.8235443 −0.2863514 3.10989568 motif- containing34A Ccl5 0.025789276 ENSMUSG00000035042 chemokine 3.1330606 1.8897779−1.2432827 3.1330606 (C-C motif) ligand 5 Phf11 0.033611197ENSMUSG00000044703 PHD finger 3.16393976 0.83319426 −2.33074553.16393976 protein 11 Sp100 6.08582E−05 ENSMUSG00000026222 nuclear3.1818978 4.8955464 1.7136486 3.1818978 antigen Sp100 Gstt1 3.95629E−06ENSMUSG00000001663 glutathione S- 3.1898814 5.8534894 2.663608 3.1898814transferase, theta 1 Irgm1 1.61702E−05 ENSMUSG00000046879 immunity-3.1988442 6.315182 3.1163378 3.1988442 related GTPase family M member 1Tnf 1.1853E−05 ENSMUSG00000024401 tumor 3.2128252 6.417355 3.20452983.2128252 necrosis factor Trib3 0.008661835 ENSMUSG00000032715 tribbles3.24853782 3.5902176 0.34167978 3.24853782 homolog 3 (Drosophila) Mcf2l0.029599534 ENSMUSG00000031442 mcf.2 3.2570492 1.0962287 −2.16082053.2570492 transforming sequence-like Gm2619 0.027174171ENSMUSG00000091199 predicted 3.27751335 2.7541227 −0.5233907 3.27751335gene 2619 Ccl2 2.73529E−05 ENSMUSG00000035385 chemokine 3.29924155.2446203 1.9453788 3.2992415 (C-C motif) ligand 2 Gm7592 0.001554758ENSMUSG00000090186 predicted 3.31135076 4.1704297 0.85907894 3.31135076gene 7592 Slamf9 0.02308799 ENSMUSG00000026548 SLAM family 3.319785062.743927 −0.5758581 3.31978506 member 9 P2ry6 0.017429588ENSMUSG00000048779 pyrimidinergic 3.3331523 2.5873692 −0.74578313.3331523 receptor P2Y, G- protein coupled, 6 Slc9a4 0.007401402ENSMUSG00000026065 solute carrier 3.3680806 2.3592632 −1.00881743.3680806 family 9 (sodium/hydrogen exchanger), member 4 Cth 1.06479E−06ENSMUSG00000028179 cystathionase 3.376959 4.760459 1.3835 3.376959(cystathionine gamma- lyase) Tmem176b 9.82651E−08 ENSMUSG00000029810transmembrane 3.4009837 6.739123 3.3381393 3.4009837 protein 176B Hao10.010638081 ENSMUSG00000027261 hydroxyacid 3.40718967 3.0306404−0.3765493 3.40718967 oxidase 1, liver Socs3 0.004106858ENSMUSG00000053113 suppressor of 3.41114926 3.8617635 0.450614243.41114926 cytokine signaling 3 Gm5431 0.03143841 ENSMUSG00000058163predicted 3.4162479 1.6704649 −1.745783 3.4162479 gene 5431 Slc7a115.55815E−05 ENSMUSG00000027737 solute carrier 3.4173804 6.2414532.8240726 3.4173804 family 7 (cationic amino acid transporter, y+system), member 11 Cd14 1.38458E−06 ENSMUSG00000051439 CD14 antigen3.428314 7.3783393 3.9500253 3.428314 Cx3cr1 0.010204745ENSMUSG00000052336 chemokine 3.45128475 3.208002 −0.2432828 3.45128475(C—X3—C) receptor 1 Gna15 0.022787878 ENSMUSG00000034792 guanine3.4586832 1.1279377 −2.3307455 3.4586832 nucleotide binding protein,alpha 15 Tifa 0.03074038 ENSMUSG00000046688 TRAF- 3.4756895 1.6043756−1.8713139 3.4756895 interacting protein with forkhead- associateddomain Slc2a6 0.007765551 ENSMUSG00000036067 solute carrier 3.48971012.4808927 −1.0088174 3.4897101 family 2 (facilitated glucosetransporter), member 6 Gm12185 0.0202251 ENSMUSG00000048852 predicted3.50280586 0.97941506 −2.5233908 3.50280586 gene 12185 Ccl22 0.01904264ENSMUSG00000031779 chemokine 3.5061447 2.8758388 −0.6303059 3.5061447(C-C motif) ligand 22 Gm7609 0.002328847 ENSMUSG00000079457 predicted3.51338906 3.937531 0.42414194 3.51338906 pseudogene 7609 9930111J21Rik10.015952412 ENSMUSG00000069893 RIKEN cDNA 3.5533596 2.8664703 −0.68688933.5533596 9930111J21 gene 1 Oas1b 0.006014395 ENSMUSG00000029605 2′-5′3.55350672 3.2227612 −0.3307455 3.55350672 oligoadenylate synthetase 1BOas2 4.47082E−05 ENSMUSG00000032690 2′-5′ 3.5568339 6.3605146 2.80368073.5568339 oligoadenylate synthetase 2 C3ar1 1.90141E−05ENSMUSG00000040552 complement 3.5586367 5.8717475 2.3131108 3.5586367component 3a receptor 1 Xk 0.016647717 ENSMUSG00000015342 Kell blood3.587198 1.0638072 −2.5233908 3.587198 group precursor (McLeodphenotype) homolog Rcsd1 0.00644401 ENSMUSG00000040723 RCSD domain3.6429406 2.2190855 −1.4238551 3.6429406 containing 1 Gm174461.97358E−07 ENSMUSG00000090648 predicted 3.6493672 6.604024 2.95465683.6493672 gene, 17446 Ms4a6c 0.012355432 ENSMUSG00000079419 membrane-3.6525339 2.022228 −1.6303059 3.6525339 spanning 4- domains, subfamilyA, member 6C Gbp3 0.00609057 ENSMUSG00000028268 guanylate 3.663919473.2873702 −0.3765493 3.66391947 binding protein 3 Irf8 0.005833246ENSMUSG00000041515 interferon 3.66485538 3.2410004 −0.423855 3.66485538regulatory factor 8 9930111J21Rik2 0.002968723 ENSMUSG00000069892 RIKENcDNA 3.66551388 3.3791625 −0.2863514 3.66551388 9930111J21 gene 2 Nxf70.026874818 ENSMUSG00000031410 nuclear RNA 3.6684755 1.6596581−2.0088174 3.6684755 export factor 7 4933421A08Rik 0.04371277ENSMUSG00000086443 RIKEN cDNA 3.6900088 −0.6407369 −4.3307457 3.69000884933421A08 gene Nfkbiz 0.000338256 ENSMUSG00000035356 nuclear factor3.69558076 4.4309244 0.73534364 3.69558076 of kappa light polypeptidegene enhancer in B-cells inhibitor, zeta Cd33 0.003050802ENSMUSG00000004609 CD33 antigen 3.7085288 3.804048 0.0955192 3.7085288Tmem132a 0.015127231 ENSMUSG00000024736 transmembrane 3.764706 2.9575224−0.8071836 3.764706 protein 132A Isg20 0.012284132 ENSMUSG00000039236interferon- 3.8299389 1.4991934 −2.3307455 3.8299389 stimulated proteinOas3 4.73984E−09 ENSMUSG00000032661 2′-5′ 3.8306523 7.3947244 3.56407213.8306523 oligoadenylate synthetase 3 Gm5483 0.03113538ENSMUSG00000079597 predicted 3.84201193 −0.4887338 −4.3307457 3.84201193gene 5483 Cd40 0.008479672 ENSMUSG00000017652 CD40 antigen 3.84939163.2190857 −0.6303059 3.8493916 Rab3il1 0.002127681 ENSMUSG00000024663RAB3A 3.8658585 2.535113 −1.3307455 3.8658585 interacting protein(rabin3)-like 1 Atf3 0.010065816 ENSMUSG00000026628 activating 3.89319043.1474073 −0.7457831 3.8931904 transcription factor 3 Neurl3 0.002695141ENSMUSG00000047180 neuralized 3.93512115 3.4117305 −0.5233907 3.93512115homolog 3 homolog (Drosophila) Gm216 0.047322746 ENSMUSG00000073650predicted 3.9351214 −1.3956243 −5.3307457 3.9351214 gene 216 Aox3l10.04825851 ENSMUSG00000079554 aldehyde 3.9351214 −1.3956243 −5.33074573.9351214 oxidase 3-like 1 Slc39a4 0.000711307 ENSMUSG00000063354 solutecarrier 3.94382097 3.5672717 −0.3765493 3.94382097 family 39 (zinctransporter), member 4 Trim30d 0.012037092 ENSMUSG00000057596 tripartite3.94794524 3.0095172 −0.938428 3.94794524 motif- containing 30D Trim30a1.61687E−07 ENSMUSG00000030921 tripartite 3.971755 6.3483686 2.37661363.971755 motif- containing 30A Cd244 0.047936272 ENSMUSG00000004709CD244 3.9940152 −1.4887338 −5.482749 3.9940152 natural killer cellreceptor 2B4 Adam33 0.048501696 ENSMUSG00000027318 a disintegrin3.9940152 −1.4887338 −5.482749 3.9940152 and metallopeptidase domain 33Art3 0.049302656 ENSMUSG00000034842 ADP- 3.9940152 −1.4887338 −5.4827493.9940152 ribosyltransferase 3 Evl 0.01699222 ENSMUSG00000021262 Ena-4.0225842 0.6918385 −3.3307457 4.0225842 vasodilator stimulatedphosphoprotein BC049352 0.019156335 ENSMUSG00000091996 cDNA 4.0225842−0.3081615 −4.3307457 4.0225842 sequence BC049352 Ms4a7 0.04587867ENSMUSG00000024672 membrane- 4.0225842 −1.3081615 −5.3307457 4.0225842spanning 4- domains, subfamily A, member 7 Cnrip1 0.04739232ENSMUSG00000044629 cannabinoid 4.0225842 −1.3081615 −5.3307457 4.0225842receptor interacting protein 1 Gbp2 0.04953059 ENSMUSG00000028270guanylate 4.0225842 −1.3081615 −5.3307457 4.0225842 binding protein 2Rbpms 0.017674573 ENSMUSG00000031586 RNA binding 4.0644043 0.7336586−3.3307457 4.0644043 protein gene with multiple splicing Leprel10.015996631 ENSMUSG00000038168 leprecan-like 1 4.06440437 −0.2663413−4.3307457 4.06440437 Adam3 0.009531343 ENSMUSG00000031553 a disintegrin4.0726246 1.0638072 −3.0088174 4.0726246 and metallopeptidase domain 3(cyritestin) Trim34b 0.007744697 ENSMUSG00000090215 tripartite 4.08079862.0719812 −2.0088174 4.0807986 motif- containing 34B Pilrb1 0.0480939ENSMUSG00000066684 paired 4.0871247 −1.3956243 −5.482749 4.0871247immunoglobin- like type 2 receptor beta 1 Prickle1 0.048321296ENSMUSG00000036158 prickle 4.0871247 −1.3956243 −5.482749 4.0871247homolog 1 (Drosophila) Ccrl2 0.048543822 ENSMUSG00000043953 chemokine4.0871247 −1.3956243 −5.482749 4.0871247 (C-C motif) receptor-like 21700003M07Rik 0.0489742 ENSMUSG00000085389 RIKEN cDNA 4.0871247−1.3956243 −5.482749 4.0871247 1700003M07 gene Nphs2 0.04948828ENSMUSG00000026602 nephrosis 2 4.0871247 −1.3956243 −5.482749 4.0871247homolog, podocin (human) Il10ra 0.003073455 ENSMUSG00000032089interleukin 10 4.10113089 4.1279373 0.02680641 4.10113089 receptor,alpha Gadd45a 0.043100644 ENSMUSG00000036390 growth arrest 4.1050463−1.2256994 −5.3307457 4.1050463 and DNA- damage- inducible 45 alpha6530402F18Rik 0.044838425 ENSMUSG00000079499 RIKEN cDNA 4.1050463−1.2256994 −5.3307457 4.1050463 6530402F18 gene Irgm2 1.04727E−05ENSMUSG00000069874 immunity- 4.1400689 4.509763 0.3696941 4.1400689related GTPase family M member 2 Gpr84 2.75089E−05 ENSMUSG00000063234 Gprotein- 4.14575538 3.859404 −0.2863514 4.14575538 coupled receptor 84Atp8b4 2.32191E−07 ENSMUSG00000060131 ATPase, class 4.1493087 6.02801661.8787079 4.1493087 I, type 8B, member 4 Pi16 0.04246121ENSMUSG00000024011 peptidase 4.1830488 −1.1476969 −5.3307457 4.1830488inhibitor 16 9430070O13Rik 0.042740114 ENSMUSG00000026601 RIKEN cDNA4.1830488 −1.1476969 −5.3307457 4.1830488 9430070O13 gene Xaf10.004594872 ENSMUSG00000040483 XIAP 4.1863461 3.3791625 −0.80718364.1863461 associated factor 1 Gbp9 0.009429601 ENSMUSG00000029298guanylate- 4.1956487 1.4498657 −2.745783 4.1956487 binding protein 9Aldh1l2 9.31273E−08 ENSMUSG00000020256 aldehyde 4.268145 6.02486231.7567173 4.268145 dehydrogenase 1 family, member L2 Ceacam19 0.01110833ENSMUSG00000049848 carcinoembryonic 4.2690218 1.5232388 −2.7457834.2690218 antigen- related cell adhesion molecule 19 Siglec1 0.000273761ENSMUSG00000027322 sialic acid 4.26931259 4.296119 0.02680641 4.26931259binding Ig-like lectin 1, sialoadhesin Nhsl1 0.007009061ENSMUSG00000039835 NHS-like 1 4.3043549 1.5585719 −2.745783 4.3043549Mx1 0.014547019 ENSMUSG00000000386 myxovirus 4.32743881 −0.0033069−4.3307457 4.32743881 (influenza virus) resistance 1 Il1b 0.038834058ENSMUSG00000027398 interleukin 1 4.3350521 −1.1476969 −5.4827494.3350521 beta Emr1 1.82451E−06 ENSMUSG00000004730 EGF-like 4.3603695.65898 1.298611 4.360369 module containing, mucin-like, hormonereceptor-like sequence 1 Parp14 1.93595E−08 ENSMUSG00000034422 poly(ADP- 4.3674735 6.3035145 1.936041 4.3674735 ribose) polymerase family,member 14 D14Ertd668e 1.30197E−05 ENSMUSG00000068245 DNA 4.368991294.4976773 0.12868601 4.36899129 segment, Chr 14, ERATO Doi 668,expressed Igtp 0.001563031 ENSMUSG00000078853 interferon 4.37734363.57016 −0.8071836 4.3773436 gamma induced GTPase Gstt4 0.011173716ENSMUSG00000009093 glutathione S- 4.3780647 2.0473192 −2.33074554.3780647 transferase, theta 4 Stap1 2.50132E−07 ENSMUSG00000029254signal 4.3900233 6.239187 1.8491637 4.3900233 transducing adaptor familymember 1 Tpbg 0.03382182 ENSMUSG00000035274 trophoblast 4.4090527−1.0736963 −5.482749 4.4090527 glycoprotein Wdr66 0.013581607ENSMUSG00000029442 WD repeat 4.45868316 0.71290016 −3.745783 4.45868316domain 66 Hunk 0.01660839 ENSMUSG00000053414 hormonally 4.489710180.15896448 −4.3307457 4.48971018 upregulated Neu- associated kinase Saa30.025470588 ENSMUSG00000040026 serum 4.5200839 −0.8106618 −5.33074574.5200839 amyloid A 3 Ifih1 7.52283E−06 ENSMUSG00000026896 interferon4.52452936 4.9486713 0.42414194 4.52452936 induced with helicase Cdomain 1 Tlr13 0.004782067 ENSMUSG00000033777 toll-like 4.54462593.3013432 −1.2432827 4.5446259 receptor 13 Trim30eps1 0.029862829ENSMUSG00000073929 tripartite 4.6106866 −0.8720624 −5.482749 4.6106866motif- containing 30E, pseudogene 1 Six4 0.006483047 ENSMUSG00000034460sine oculis- 4.63556084 0.88977784 −3.745783 4.63556084 related homeobox4 homolog (Drosophila) Cybb 1.95579E−07 ENSMUSG00000015340 cytochrome4.7431125 5.752217 1.0091045 4.7431125 b-245, beta polypeptide BC0137120.000281571 ENSMUSG00000037731 cDNA 4.7587783 3.8874643 −0.8713144.7587783 sequence BC013712 Galnt3 0.00355866 ENSMUSG00000026994 No4.7595498 2.0137668 −2.745783 4.7595498 description Tnnt2 0.02091825ENSMUSG00000026414 troponin T2, 4.7875644 −0.6951846 −5.482749 4.7875644cardiac Fabp4 0.021602802 ENSMUSG00000062515 fatty acid 4.7875644−0.6951846 −5.482749 4.7875644 binding protein 4, adipocyte Slpi0.01807874 ENSMUSG00000017002 secretory 4.7931023 0.4623566 −4.33074574.7931023 leukocyte peptidase inhibitor Ifi44 1.53211E−14ENSMUSG00000028037 interferon- 4.8898906 8.224481 3.3345904 4.8898906induced protein 44 AI504432 0.019602522 ENSMUSG00000056145 expressed4.8944795 −0.5882695 −5.482749 4.8944795 sequence AI504432 Ddx600.000261457 ENSMUSG00000037921 DEAD (Asp- 4.923806 3.178023 −1.7457834.923806 Glu-Ala-Asp) box polypeptide 60 Slc9a9 0.020172823ENSMUSG00000031129 solute carrier 4.9451056 −0.5376434 −5.4827494.9451056 family 9 (sodium/hydrogen exchanger), member 9 Ccl70.000610965 ENSMUSG00000035373 chemokine 4.9591955 3.3288896 −1.63030594.9591955 (C-C motif) ligand 7 Ddx58 3.12944E−11 ENSMUSG00000040296 DEAD(Asp- 4.9671744 7.1678104 2.200636 4.9671744 Glu-Ala-Asp) boxpolypeptide 58 I830012O16Rik 0.004567375 ENSMUSG00000062488 RIKEN cDNA4.9940149 1.2482319 −3.745783 4.9940149 I830012O16 gene Irf7 8.24433E−07ENSMUSG00000025498 interferon 5.01074876 5.4348907 0.42414194 5.01074876regulatory factor 7 Htra4 0.017311335 ENSMUSG00000037406 HtrA serine5.04132096 −0.441428 −5.482749 5.04132096 peptidase 4 Siglece 0.00169967ENSMUSG00000030474 sialic acid 5.0807986 2.0719812 −3.0088174 5.0807986binding Ig-like lectin E Aqp9 0.000577649 ENSMUSG00000032204 aquaporin 95.088251 3.342468 −1.745783 5.088251 Adh7 0.002669529 ENSMUSG00000055301alcohol 5.1050461 1.3592631 −3.745783 5.1050461 dehydrogenase 7 (classIV), mu or sigma polypeptide Slc30a2 0.014447143 ENSMUSG00000028836solute carrier 5.10504635 −0.2256994 −5.3307457 5.10504635 family 30(zinc transporter), member 2 Cd86 0.00104289 ENSMUSG00000022901 CD86antigen 5.1249457 2.7942002 −2.3307455 5.1249457 Hsh2d 0.009497254ENSMUSG00000062007 hematopoietic 5.16393996 0.83319426 −4.33074575.16393996 SH2 domain containing Ccnd2 0.000857036 ENSMUSG00000000184cyclin D2 5.1779776 3.7541225 −1.4238551 5.1779776 Asb2 0.008776278ENSMUSG00000021200 ankyrin 5.1830489 0.8523032 −4.3307457 5.1830489repeat and SOCS box- containing 2 Gm1966 0.009493642 ENSMUSG00000073902predicted 5.20190794 0.87116224 −4.3307457 5.20190794 gene 1966 Col14a10.012412123 ENSMUSG00000022371 collagen, type 5.21640767 −0.2663413−5.482749 5.21640767 XIV, alpha 1 Clec4a1 0.003088675 ENSMUSG00000049037C-type lectin 5.2205235 2.4747405 −2.745783 5.2205235 domain family 4,member a1 Gm11711 0.000704584 ENSMUSG00000089722 predicted 5.29267342.7692826 −2.5233908 5.2926734 gene 11711 Gbp5 0.012722499ENSMUSG00000040264 guanylate 5.29657803 −0.186171 −5.482749 5.29657803binding protein 5 Gm11710 0.000707052 ENSMUSG00000069609 predicted5.2976914 2.7743006 −2.5233908 5.2976914 gene 11710 Cd300lh 0.000719966ENSMUSG00000069607 CD300 5.3026922 2.7793014 −2.5233908 5.3026922antigen like family member H Kcna3 0.007314483 ENSMUSG00000047959potassium 5.36138606 0.03064036 −5.3307457 5.36138606 voltage-gatedchannel, shaker- related subfamily, member 3 Niacr1 0.000542988ENSMUSG00000045502 niacin 5.3709405 2.8475497 −2.5233908 5.3709405receptor 1 Dhx58 1.07756E−08 ENSMUSG00000017830 DEXH (Asp- 5.411377275.034828 −0.3765493 5.41137727 Glu-X-His) box polypeptide 58 Cmpk21.21268E−06 ENSMUSG00000020638 cytidine 5.42365352 4.950889 −0.47276455.42365352 monophosphate (UMP- CMP) kinase 2, mitochondrial Irak30.000561619 ENSMUSG00000020227 interleukin-1 5.4246825 3.9012918−1.5233907 5.4246825 receptor- associated kinase 3 Lysmd2 0.007453424ENSMUSG00000032184 LysM, 5.42697442 0.09622872 −5.3307457 5.42697442putative peptidoglycan- binding, domain containing 2 Cxcl10 0.000436733ENSMUSG00000034855 chemokine 5.4269746 2.9035838 −2.5233908 5.4269746(C—X—C motif) ligand 10 C5ar1 8.91278E−05 ENSMUSG00000049130 complement5.4794421 4.055587 −1.4238551 5.4794421 component 5a receptor 1 Ifit20.000635787 ENSMUSG00000045932 interferon- 5.4802343 3.8499284−1.6303059 5.4802343 induced protein with tetratricopeptide repeats 2Gm15655 0.009071947 ENSMUSG00000086717 predicted 5.51338936 0.03064036−5.482749 5.51338936 gene 15655 Apol9b 0.000853888 ENSMUSG00000057346apolipoprotein 5.5350342 2.2042885 −3.3307457 5.5350342 L 9b4930438A08Rik 0.008135167 ENSMUSG00000069873 RIKEN cDNA 5.546556320.06380732 −5.482749 5.54655632 4930438A08 gene Slamf7 0.008154977ENSMUSG00000038179 SLAM family 5.54655632 0.06380732 −5.4827495.54655632 member 7 Trem3 0.007723238 ENSMUSG00000041754 triggering5.57897772 0.09622872 −5.482749 5.57897772 receptor expressed on myeloidcells 3 Il10 0.006503063 ENSMUSG00000016529 interleukin 10 5.610686660.12793766 −5.482749 5.61068666 Itga9 0.006992263 ENSMUSG00000039115integrin alpha 9 5.61068666 0.12793766 −5.482749 5.61068666 Rnase40.000401531 ENSMUSG00000021876 ribonuclease, 5.7743251 2.4435794−3.3307457 5.7743251 RNase A family 4 Rtp4 2.66731E−08ENSMUSG00000033355 receptor 5.78130823 5.6204877 −0.1608205 5.78130823transporter protein 4 Itgal 8.11603E−08 ENSMUSG00000030830 integrinalpha L 5.80660638 5.520255 −0.2863514 5.80660638 Isg15 4.77137E−05ENSMUSG00000035692 ISG15 5.8244175 4.9531035 −0.871314 5.8244175ubiquitin-like modifier Cd300e 0.000227213 ENSMUSG00000048498 CD300e5.9200143 2.1742313 −3.745783 5.9200143 antigen Zbp1 0.000939954ENSMUSG00000027514 Z-DNA 5.9463487 1.615603 −4.3307457 5.9463487 bindingprotein 1 Ifit3 0.00091502 ENSMUSG00000074896 interferon- 5.95748911.6267434 −4.3307457 5.9574891 induced protein with tetratricopeptiderepeats 3 Gpr65 8.52311E−06 ENSMUSG00000021886 G-protein 5.98496973.6542242 −2.3307455 5.9849697 coupled receptor 65 Gm11428 0.001755864ENSMUSG00000069792 predicted 6.04132093 0.55857193 −5.482749 6.04132093gene 11428 Ccl4 8.01905E−11 ENSMUSG00000018930 chemokine 6.043645546.54579 0.50214446 6.04364554 (C-C motif) ligand 4 Gm14085 0.000702213ENSMUSG00000079071 predicted 6.0644043 0.7336586 −5.3307457 6.0644043gene 14085 Lcn2 0.000630766 ENSMUSG00000026822 lipocalin 2 6.21640760.7336586 −5.482749 6.2164076 Apol9a 0.000453771 ENSMUSG00000068246apolipoprotein 6.2660382 2.9352925 −3.3307457 6.2660382 L 9a Tnfrsf13b0.000442462 ENSMUSG00000010142 tumor 6.3317263 3.0009806 −3.33074576.3317263 necrosis factor receptor superfamily, member 13b Maf3.9675E−06 ENSMUSG00000055435 avian 6.3557831 3.6100001 −2.7457836.3557831 musculoaponeurotic fibrosarcoma (v-maf) AS42 oncogene homologGm4070 9.03925E−07 ENSMUSG00000078606 predicted 6.3693103 5.2864923−1.082818 6.3693103 gene 4070 Gvin1 7.25705E−07 ENSMUSG00000045868GTPase, very 6.3885 5.305682 −1.082818 6.3885 large interferon inducible1 Usp18 4.19049E−11 ENSMUSG00000030107 ubiquitin 6.46699962 6.6908430.22384338 6.46699962 specific peptidase 18 Slc28a2 0.000986595ENSMUSG00000027219 solute carrier 6.564478 1.2337323 −5.3307457 6.564478family 28 (sodium- coupled nucleoside transporter), member 2 Slc15a31.36526E−11 ENSMUSG00000024737 solute carrier 6.58377798 6.159923−0.423855 6.58377798 family 15, member 3 Gm11547 0.000421104ENSMUSG00000085604 predicted 6.6106867 1.1279377 −5.482749 6.6106867gene 11547 Il18rap 1.85857E−05 ENSMUSG00000026068 interleukin 186.6765883 2.3458426 −4.3307457 6.6765883 receptor accessory protein2010002M12Rik 0.000675854 ENSMUSG00000067297 RIKEN cDNA 6.74533611.2625871 −5.482749 6.7453361 2010002M12 gene Batf 0.00066985ENSMUSG00000034266 basic leucine 6.75955 1.276801 −5.482749 6.75955zipper transcription factor, ATF- like Irg1 3.31171E−11ENSMUSG00000022126 immunoresponsive 6.81480982 6.3420453 −0.47276456.81480982 gene 1 Serinc2 0.000244017 ENSMUSG00000023232 serine6.8737206 3.1279376 −3.745783 6.8737206 incorporator 2 Csf3 0.001778822ENSMUSG00000038067 colony 6.9351213 1.6043756 −5.3307457 6.9351213stimulating factor 3 (granulocyte) Gm14275 0.001133265ENSMUSG00000085949 predicted 6.9451056 1.4623566 −5.482749 6.9451056gene 14275 H28 1.20005E−05 ENSMUSG00000039146 histocompatibility6.9781485 4.647403 −2.3307455 6.9781485 28 Gm11709 0.001331092ENSMUSG00000089753 predicted 7.0012106 1.6704649 −5.3307457 7.0012106gene 11709 Cxcl2 6.37467E−06 ENSMUSG00000058427 chemokine 7.03615914.5127683 −2.5233908 7.0361591 (C—X—C motif) ligand 2 Gm8979 0.000989941ENSMUSG00000091928 predicted 7.226676 1.743927 −5.482749 7.226676 gene8979 Gm8989 0.001071625 ENSMUSG00000091567 predicted 7.226676 1.743927−5.482749 7.226676 gene 8989 Lgals9 1.50607E−06 ENSMUSG00000001123lectin, 7.357186 4.611403 −2.745783 7.357186 galactose binding, soluble9 Rsad2 2.21866E−08 ENSMUSG00000020641 radical S- 7.438284 5.692501−1.745783 7.438284 adenosyl methionine domain containing 2 Oasl20.000192137 ENSMUSG00000029561 2′-5′ 7.5275784 2.1968327 −5.33074577.5275784 oligoadenylate synthetase- like 2 Zfp811 0.00022262ENSMUSG00000055202 zinc finger 7.5869706 2.1042216 −5.482749 7.5869706protein 811 Lancl3 1.56193E−05 ENSMUSG00000047344 LanC 7.78061132.4498656 −5.3307457 7.7806113 lantibiotic synthetase component C-like 3(bacterial) Ppfibp2 1.1878E−06 ENSMUSG00000036528 PTPRF 7.83498165.0891986 −2.745783 7.8349816 interacting protein, binding protein 2(liprin beta 2) Mx2 2.73356E−05 ENSMUSG00000023341 myxovirus 7.85398472.523239 −5.3307457 7.8539847 (influenza virus) resistance 2 Pou2f25.15218E−06 ENSMUSG00000008496 POU domain, 8.2065845 2.8758388−5.3307457 8.2065845 class 2, transcription factor 2 Ifit1 8.33396E−06ENSMUSG00000034459 interferon- 8.227443 3.8966973 −4.3307457 8.227443induced protein with tetratricopeptide repeats 1 Nos2 2.15861E−09ENSMUSG00000020826 nitric oxide 8.6715229 6.3407774 −2.3307455 8.6715229synthase 2, inducible Fcgr1 1.58442E−08 ENSMUSG00000015947 Fc receptor,8.9574893 3.4747403 −5.482749 8.9574893 IgG, high affinity I

TABLE 2 log₂ normalized Read count NCsh NCsh MMP-9sh MMP-9sh log₂ ratioNCsh Peak Gene (N) (C) (N) (C) Input (N) vs input Promoter CleavageChr1:129640001- Acmsd 3.452 3.345 3.723 4.892 4.644 −1.192 129641000Chr1:130156001- Ubxn4 2.867 3.831 4.045 3.754 3.907 −1.040 130157000Chr1:132640001- AA986860 2.452 3.345 3.308 4.240 3.585 −1.133 132641000Chr1:132971001- Mapkapk2 2.867 4.608 3.308 4.602 3.907 −1.040 132972000Chr1:134423001- Cntn2 1.867 1.023 4.308 1.433 3.459 −1.592 134424000Chr1:135147001- Plekha6 2.452 3.608 3.308 3.754 3.459 −1.007 135148000Chr1:136022001- Chit1 3.189 4.193 4.893 4.754 4.585 −1.396 136023000Chr1:155379001- Npl 1.867 4.345 2.723 3.017 3.322 −1.455 155380000Chr1:173073001- Sdhc 2.452 3.608 3.308 4.433 4.000 −1.548 173074000Chr1:175560001- Pyhin1 1.867 4.608 3.723 2.433 3.700 −1.833 175561000Chr1:179681001- 1700016C15Rik 2.867 4.345 4.723 3.433 4.248 −1.381179682000 Chr1:182164001- Psen2 2.867 3.023 3.723 4.017 3.907 −1.040182165000 Chr1:184064001- Srp9 2.867 3.831 3.723 4.240 4.170 −1.303184065000 Chr1:188482001- Tgfb2 1.867 3.608 1.723 3.433 3.807 −1.940188483000 Chr1:193904001- Traf5 1.867 3.345 2.723 3.017 3.807 −1.940193905000 Chr1:74383001- Pnkd 2.867 3.345 3.723 4.017 3.907 −1.04074384000 Chr1:87941001- 2810459M11Rik 2.452 3.345 3.723 3.754 4.000−1.548 87942000 Chr1:89474001- Neu2 3.452 4.345 5.308 3.017 4.524 −1.07289475000 Chr1:90985001- Sh3bp4 1.867 3.345 1.723 3.433 3.000 −1.13390986000 Chr10:126473001- Fam119b 2.452 3.345 4.045 3.017 3.459 −1.007126474000 Chr10:127188001- Gpr182 1.867 4.193 3.308 4.240 3.907 −2.040127189000 Chr10:127669001- Gm17292 0.867 3.608 1.723 3.433 2.000 −1.133127670000 Chr10:127719001- Stat2 3.189 3.023 3.308 4.892 4.322 −1.133127720000 Chr10:127753001- Pan2 1.867 2.608 3.308 4.017 3.322 −1.455127754000 Chr10:128362001- Bloc1s1 2.452 2.023 4.308 3.754 4.392 −1.940128363000 Chr10:18728001- Tnfaip3 2.452 3.345 3.308 4.017 4.248 −1.79618729000 Chr10:39706001- BC021785 2.452 3.608 3.308 4.017 3.700 −1.24839707000 Chr10:79539001- Sbno2 2.867 3.345 1.723 4.754 4.087 −1.22079540000 Chr10:80327001- 3110056O03Rik 2.452 2.023 3.723 3.754 3.585−1.133 80328000 Chr10:80619001- Pias4 1.867 3.608 3.308 2.433 4.000−2.133 80620000 Chr10:80643001- Eef2 2.452 3.345 3.723 4.017 3.700−1.248 80644000 Chr10:83993001- Ckap4 2.452 2.608 4.045 4.602 3.585−1.133 83994000 Chr10:95254001- 4732465J04Rik 2.867 4.608 4.723 3.4334.170 −1.303 95255000 Chr11:105800001- Cyb561 2.452 3.345 1.571 4.7543.585 −1.133 105801000 Chr11:113519001- Cog1 0.867 4.023 2.723 3.4332.000 −1.133 113520000 Chr11:11402001- 4930415F15Rik 2.867 4.023 3.3084.433 3.907 −1.040 11403000 Chr11:114860001- AF251705 0.867 3.345 2.7234.017 3.170 −2.303 114861000 Chr11:115269001- Ict1 2.452 4.023 3.7233.754 3.907 −1.455 115270000 Chr11:115756001- Recql5 2.867 3.608 3.7234.017 3.907 −1.040 115757000 Chr11:116715001- 1110005A03Rik 2.452 4.0234.531 3.754 3.807 −1.355 116716000 Chr11:120209001- Actg1 1.867 3.0231.723 3.433 3.170 −1.303 120210000 Chr11:120807001- Slc16a3 1.867 3.3454.308 4.017 3.322 −1.455 120808000 Chr11:20235001- Gm12033 2.452 3.6083.308 3.754 4.807 −2.355 20236000 Chr11:4600001- Uqcr10 2.867 3.3451.723 4.602 4.000 −1.133 4601000 Chr11:48668001- Gm16170 2.867 4.0234.723 4.892 4.248 −1.381 48669000 Chr11:50020001- Sqstm1 2.452 3.0233.723 3.754 3.585 −1.133 50021000 Chr11:53698001- Slc22a5 1.867 2.0231.723 3.433 3.907 −2.040 53699000 Chr11:5423001- Xbp1 2.452 4.193 4.3084.240 3.807 −1.355 5424000 Chr11:54967001- Slc36a3 2.452 3.608 4.0453.017 3.700 −1.248 54968000 Chr11:55071001- Fat2 2.867 4.023 1.571 4.7544.087 −1.220 55072000 Chr11:55268001- Atox1 1.867 3.345 3.723 1.4333.807 −1.940 55269000 Chr11:58748001- Rnf187 2.867 4.193 3.723 4.0174.087 −1.220 58749000 Chr11:61037001- Aldh3a2 2.867 3.831 3.308 4.2404.000 −1.133 61038000 Chr11:61368001- Epn2 2.867 3.608 3.308 4.240 3.907−1.040 61369000 Chr11:61523001- Slc5a10 2.867 3.831 4.308 3.433 3.907−1.040 61524000 Chr11:62119001- Ttc19 3.189 3.831 4.531 4.017 4.248−1.059 62120000 Chr11:62467001- Mmgt2 2.452 3.023 3.308 4.240 3.907−1.455 62468000 Chr11:6381001- Gm11973 1.867 3.023 3.308 3.754 3.807−1.940 6382000 Chr11:69468001- Sox15 2.452 2.608 4.531 2.433 4.170−1.718 69469000 Chr11:69660001- Plscr3 1.867 3.345 3.723 3.433 3.170−1.303 69661000 Chr11:76842001- Slc6a4 1.867 3.345 1.723 3.433 3.807−1.940 76843000 Chr11:77314001- Git1 2.452 4.345 5.045 3.754 3.700−1.248 77315000 Chr11:82996001- Slfn4 2.867 4.345 3.723 4.433 4.000−1.133 82997000 Chr11:87493001- Rnf43 2.867 3.023 3.723 4.017 4.644−1.777 87494000 Chr11:88591001- C030037D09Rik 2.452 2.023 3.308 4.0173.700 −1.248 88592000 Chr11:95724001- 4833417C18Rik 1.867 4.608 2.7234.240 3.700 −1.833 95725000 Chr11:95903001- Snf8 2.867 2.608 3.723 4.7544.000 −1.133 95904000 Chr11:95910001- Ube2z 2.867 4.193 3.308 4.2404.087 −1.220 95911000 Chr11:96710001- Copz2 2.452 3.345 4.045 3.0173.907 −1.455 96711000 Chr12:102171001- Ccdc88c 2.867 4.023 3.308 4.2403.907 −1.040 102172000 Chr12:112921001- Trmt61a 1.867 3.608 3.308 3.0173.807 −1.940 112922000 Chr12:113739001- Tmem179 1.867 4.023 1.723 4.2403.907 −2.040 113740000 Chr12:17888001- Gm9222 1.867 3.023 1.723 3.4334.000 −2.133 17889000 Chr12:17933001- B430203G13Rik 1.867 3.608 3.7233.754 4.459 −2.592 17934000 Chr12:27159001- Cmpk2 2.452 3.608 3.7233.433 3.585 −1.133 27160000 Chr12:82636001- 6530401F13Rik 2.452 3.6084.045 3.754 3.700 −1.248 82637000 Chr12:85359001- Acot1 2.452 3.6084.045 4.017 4.524 −2.072 85360000 Chr12:86814001- Fos 2.452 3.345 4.0453.017 3.585 −1.133 86815000 Chr13:104825001- Nln 1.867 4.023 3.308 2.4334.087 −2.220 104826000 Chr13:34334001- Slc22a23 2.867 3.831 4.308 3.4333.907 −1.040 34335000 Chr13:54890001- Tspan17 2.452 3.345 3.723 3.4333.700 −1.248 54891000 Chr13:55882001- 4930451E10Rik 3.452 4.608 5.0454.017 4.700 −1.248 55883000 Chr13:65364001- Gm10775 1.867 3.345 2.7233.017 3.322 −1.455 65365000 Chr13:70147001- Gm6132 1.867 3.345 1.5714.017 3.170 −1.303 70148000 Chr13:74444001- Pdcd6 0.867 3.831 4.5313.017 3.700 −2.833 74445000 Chr13:8940001- Rpl10a-ps2 2.452 3.023 4.0454.602 3.700 −1.248 8941000 Chr13:8955001- Idi2 0.867 3.345 3.723 4.0173.000 −2.133 8956000 Chr13:94943001- Lhfpl2 1.867 4.023 2.723 3.0173.585 −1.718 94944000 Chr13:96004001- Pde8b 2.867 0.871 3.723 4.0173.907 −1.040 96005000 Chr14:20414001- Gm5458 2.452 4.023 4.045 3.7544.170 −1.718 20415000 Chr14:25130001- E330034G19Rik 2.452 3.345 4.0453.017 4.000 −1.548 25131000 Chr14:31752001- Itih1 2.867 3.023 2.7234.602 4.000 −1.133 31753000 Chr14:4733001- Gm8159 2.452 4.831 4.3083.017 4.000 −1.548 4734000 Chr14:47392001- Cdkn3 2.867 4.023 3.723 4.0174.000 −1.133 47393000 Chr14:55248001- Psmb11 3.189 1.023 4.045 4.4334.248 −1.059 55249000 Chr14:55260001- Cdh24 1.867 3.608 2.723 3.0173.000 −1.133 55261000 Chr14:55473001- Homez 0.867 4.193 4.045 3.0173.585 −2.718 55474000 Chr14:59880001- Gm6904 1.867 4.345 4.308 3.4333.585 −1.718 59881000 Chr14:59986001- D14Ertd668e 2.452 4.023 4.3084.017 3.807 −1.355 59987000 Chr14:62086001- Rps12-ps2 2.452 3.023 4.3084.017 3.907 −1.455 62087000 Chr14:8296001- Gm3752 2.867 3.345 3.7234.017 4.000 −1.133 8297000 Chr14:8390001- Gm3558 2.867 3.608 4.045 3.7543.907 −1.040 8391000 Chr15:101942001- Tenc1 1.867 3.608 3.723 2.4333.000 −1.133 101943000 Chr15:10441001- Ttc23l 1.867 4.023 1.723 3.4333.322 −1.455 10442000 Chr15:52159001- Slc30a8 2.452 4.345 4.045 3.0173.700 −1.248 52160000 Chr15:73341001- Dennd3 2.867 2.608 4.045 3.7544.585 −1.718 73342000 Chr15:74714001- 2010109I03Rik 2.452 3.608 4.0454.240 3.585 −1.133 74715000 Chr15:79783001- Cbx7 1.867 3.023 3.308 2.4333.459 −1.592 79784000 Chr15:85660001- Ttc38 1.867 1.023 2.723 3.0173.807 −1.940 85661000 Chr15:88950001- Tubgcp6 1.867 3.608 4.045 3.7543.700 −1.833 88951000 Chr15:9054001- Skp2 2.452 3.608 4.045 3.433 4.087−1.635 9055000 Chr16:11128001- Txndc11 2.867 4.483 3.308 4.240 4.087−1.220 11129000 Chr16:16417001- Fgd4 2.867 3.023 3.723 4.017 4.170−1.303 16418000 Chr16:18632001- SEPT_5 2.452 4.023 4.045 4.017 3.459−1.007 18633000 Chr16:32683001- Tnk2 2.867 4.023 4.045 3.754 4.000−1.133 32684000 Chr16:38321001- 4932425I24Rik 2.452 3.023 3.723 4.0173.585 −1.133 38322000 Chr16:44176001- Gm608 2.867 4.930 3.723 4.0174.087 −1.220 44177000 Chr16:77117001- Usp25 3.452 3.831 4.531 4.4334.954 −1.502 77118000 Chr16:85795001- Adamts1 2.867 4.023 2.723 4.7543.907 −1.040 85796000 Chr16:8850001- 1810013L24Rik 2.452 4.345 3.3083.754 3.459 −1.007 8851000 Chr16:93610001- Cbr1 2.867 4.193 4.531 3.7544.170 −1.303 93611000 Chr16:94735001- Dscr3 2.867 4.023 3.723 4.0174.000 −1.133 94736000 Chr17:21685001- Zfp52 3.452 4.023 4.531 4.4334.700 −1.248 21686000 Chr17:24229001- Pdpk1 2.452 4.483 2.723 4.0173.459 −1.007 24230000 Chr17:24373001- Ccnf 3.189 1.023 2.723 5.133 4.322−1.133 24374000 Chr17:24873001- Rpl3l 1.867 3.023 3.308 3.754 3.459−1.592 24874000 Chr17:27033001- Gm20468 2.452 3.023 4.308 4.017 3.459−1.007 27034000 Chr17:27740001- Nudt3 3.452 3.608 4.045 5.017 4.524−1.072 27741000 Chr17:27816001- Pacsin1 1.867 4.023 2.723 3.017 3.459−1.592 27817000 Chr17:34072001- Rgl2 0.867 3.345 2.723 2.433 3.807−2.940 34073000 Chr17:35619001- Gm20419 2.452 3.608 3.723 3.754 4.322−1.870 35620000 Chr17:37004001- Trim15 1.867 3.345 2.723 3.433 3.322−1.455 37005000 Chr17:48573001- Apobec2 0.715 3.023 1.723 4.240 3.000−2.285 48574000 Chr17:53812001- Kat2b 1.867 2.608 2.723 3.017 3.322−1.455 53813000 Chr17:57010001- Acsbg2 1.867 3.608 1.723 3.433 3.322−1.455 57011000 Chr17:57392001- Trip10 2.452 3.023 4.723 2.433 3.700−1.248 57393000 Chr17:66342001- Ankrd12 1.867 3.345 1.571 3.754 3.000−1.133 66343000 Chr17:6857001- Dynlt1e 2.452 3.608 4.045 3.754 3.700−1.248 6858000 Chr17:71251001- Gm16627 2.867 3.831 4.045 3.754 3.907−1.040 71252000 Chr17:80944001- Cdkl4 1.867 3.345 3.723 1.433 3.459−1.592 80945000 Chr17:8170001- Rsph3a 1.867 3.831 3.308 2.433 3.807−1.940 8171000 Chr17:85187001- Lrpprc 2.867 3.831 4.308 3.433 3.907−1.040 85188000 Chr18:35942001- Ube2d2 2.452 4.023 1.723 4.240 3.459−1.007 35943000 Chr18:37655001- Pcdhb19 2.452 3.023 1.723 4.602 3.700−1.248 37656000 Chr18:50200001- Tnfaip8 2.867 3.831 3.723 4.017 4.000−1.133 50201000 Chr18:57047001- MARCH_3 2.452 4.483 4.308 3.017 3.700−1.248 57048000 Chr18:60427001- Gm4841 2.452 3.345 4.045 4.017 4.000−1.548 60428000 Chr18:74948001- Acaa2 2.452 3.023 3.723 3.433 4.170−1.718 74949000 Chr18:80213001- Gm10527 2.452 0.871 3.308 3.754 3.459−1.007 80214000 Chr18:80911001- Nfatc1 0.867 3.860 2.723 3.433 3.170−2.303 80812000 Chr19:10603001- Cpsf7 2.867 3.023 3.308 4.602 3.907−1.040 10604000 Chr19:11531001- Ms4a4b 2.867 3.831 5.531 3.017 3.907−1.040 11532000 Chr19:11848001- Mrpl16 1.867 2.608 4.308 2.433 3.322−1.455 11849000 Chr19:23147001- C330002G04Rik 2.452 3.345 2.723 4.0173.585 −1.133 23148000 Chr19:29102001- Ak3 2.452 4.345 3.308 4.017 3.807−1.355 29103000 Chr19:41984001- Pgam1 1.867 4.193 1.723 3.433 3.322−1.455 41985000 Chr19:42219001- Marveld1 3.189 3.831 3.723 4.602 4.392−1.203 42220000 Chr19:4234001- Pold4 1.867 3.608 2.723 3.017 3.459−1.592 4235000 Chr19:47606001- Obfc1 1.867 4.193 3.308 2.433 3.322−1.455 47607000 Chr19:5418001- 4930481A15Rik 2.452 3.831 4.045 3.0173.585 −1.133 5419000 Chr19:5600001- Rnaseh2c 1.867 4.483 3.308 4.0173.459 −1.592 5601000 Chr19:60628001- 2700078E11Rik 2.452 4.345 3.7233.754 3.700 −1.248 60629000 Chr19:6064001- Tm7sf2 2.867 3.345 4.0453.754 4.000 −1.133 6065000 Chr19:6314001- Cdc42bpg 0.867 4.023 3.3084.240 3.000 −2.133 6315000 Chr19:7075001- Fermt3 2.452 4.345 4.045 3.0173.459 −1.007 7076000 Chr2:103928001- Cd59b 3.189 3.608 3.723 4.892 4.585−1.396 103929000 Chr2:112164001- Slc12a6 2.867 3.831 4.308 3.433 4.807−1.940 112165000 Chr2:117160001- Rasgrp1 2.867 3.023 3.308 4.433 3.907−1.040 117161000 Chr2:119428001- 1700020I14Rik 2.452 2.608 3.723 4.4333.459 −1.007 119429000 Chr2:126901001- Blvra 2.867 4.023 3.723 4.0175.392 −2.525 126902000 Chr2:152565001- Id1 1.867 2.608 3.723 3.017 3.000−1.133 152566000 Chr2:154497001- Chmp4b 2.867 4.023 4.308 3.433 4.248−1.381 154498000 Chr2:155358001- Acss2 2.867 3.608 3.308 4.240 3.907−1.040 155359000 Chr2:155416001- Gss 2.452 3.608 3.723 4.017 4.000−1.548 155417000 Chr2:156658001- Gm14230 0.867 4.193 3.308 4.602 2.000−1.133 156659000 Chr2:158083001- Bpi 0.867 3.023 2.723 3.017 3.807−2.940 158084000 Chr2:164300001- Sys1 3.189 4.193 4.308 4.433 4.322−1.133 164301000 Chr2:164595001- Gm11457 1.867 3.608 1.723 4.602 3.000−1.133 164596000 Chr2:167439001- Ube2v1 2.452 3.023 2.723 4.017 3.585−1.133 167440000 Chr2:172260001- Gm14455 1.867 5.023 4.045 2.433 3.585−1.718 172261000 Chr2:17959001- A930004D18Rik 0.867 2.608 3.308 3.4333.459 −2.592 17960000 Chr2:21137001- Thnsl1 2.452 4.608 4.531 2.4333.459 −1.007 21138000 Chr2:24198001- Il1rn 2.867 4.608 4.531 4.240 4.087−1.220 24199000 Chr2:25034001- Nrarp 1.867 2.608 2.723 4.017 3.459−1.592 25035000 Chr2:26800001- Gm711 2.452 3.831 3.723 3.433 4.644−2.192 26801000 Chr2:26870001- 5930434B04Rik 2.452 3.608 3.723 3.4333.807 −1.355 26871000 Chr2:30817001- Tor1a 1.867 3.831 3.308 3.017 3.700−1.833 30818000 Chr2:3231001- Nmt2 1.867 4.023 3.308 2.433 3.000 −1.1333232000 Chr2:33583001- Fam125b 1.867 4.193 3.308 2.433 3.322 −1.45533584000 Chr2:34532001- Gapvd1 2.867 4.724 4.045 3.754 3.907 −1.04034533000 Chr2:36078001- Gm13431 1.867 3.345 3.723 2.433 3.000 −1.13336079000 Chr2:38383001- Nek6 1.867 3.831 3.308 2.433 3.322 −1.45538384000 Chr2:56967001- Nr4a2 1.867 4.193 1.723 4.433 3.000 −1.13356968000 Chr2:60076001- MARCH_7 2.867 4.023 3.723 4.017 4.000 −1.13360077000 Chr2:84647001- Ube2l6 0.715 2.608 2.723 2.433 2.807 −2.09284648000 Chr2:90741001- Ndufs3 1.867 4.345 2.723 3.017 3.322 −1.45590742000 Chr2:90894001- Gm13778 2.452 4.023 3.723 3.433 3.459 −1.00790895000 Chr2:90910001- Slc39a13 1.867 3.608 4.308 1.280 3.000 −1.13390911000 Chr2:91154001- 1110051M20Rik 2.867 3.023 4.723 2.433 4.000−1.133 91155000 Chr2:93026001- Trp53i11 2.452 4.023 3.723 3.433 3.585−1.133 93027000 Chr3:145309001- Cyr61 2.452 3.608 2.723 4.017 3.700−1.248 145310000 Chr3:14610001- 1810022K09Rik 2.452 3.608 4.045 3.7544.000 −1.548 14611000 Chr3:31061001- Cldn11 1.867 3.345 2.723 3.4333.000 −1.133 31062000 Chr3:32336001- Pik3ca 1.867 3.345 3.723 1.4333.170 −1.303 32337000 Chr3:33703001- Ttc14 2.452 3.831 2.723 4.017 3.807−1.355 33704000 Chr3:51236001- Naa15 2.452 4.023 2.723 4.017 3.700−1.248 51237000 Chr3:90190001- Slc27a3 2.867 4.023 4.531 3.017 4.392−1.525 90191000 Chr3:90203001- Ints3 3.452 4.345 4.045 4.892 4.524−1.072 90204000 Chr4:107892001- Zyg11a 2.452 4.193 4.045 3.017 3.807−1.355 107893000 Chr4:116776001- Ptch2 1.867 3.345 3.308 2.433 3.585−1.718 116777000 Chr4:117548001- B4galt2 1.867 3.023 1.723 3.754 4.000−2.133 117549000 Chr4:119308001- Guca2a 0.867 4.345 2.723 2.433 3.459−2.592 119309000 Chr4:128582001- Trim62 2.452 4.193 3.723 3.754 3.459−1.007 128583000 Chr4:143208001- Gm13083 2.452 3.831 3.723 4.017 3.700−1.248 143209000 Chr4:143946001- Gm13119 2.452 3.345 3.308 3.754 3.459−1.007 143947000 Chr4:14616001- Lrrc69 3.189 4.724 4.308 4.240 4.322−1.133 14617000 Chr4:149467001- Gpr157 2.452 2.023 4.045 3.433 3.807−1.355 149468000 Chr4:150276001- Park7 2.867 3.023 3.308 4.240 4.000−1.133 150277000 Chr4:19525001- Fam82b 2.867 3.831 3.723 4.240 3.907−1.040 19526000 Chr4:40995001- Aqp7 2.452 4.345 2.723 4.240 3.807 −1.35540996000 Chr4:41472001- 2310028H24Rik 1.867 4.345 1.723 3.754 3.322−1.455 41473000 Chr4:45357001- Dcaf10 2.867 3.345 3.723 4.017 4.000−1.133 45358000 Chr4:49546001- Zfp189 2.452 3.831 3.723 3.433 3.700−1.248 49547000 Chr4:53802001- Tal2 2.867 3.831 4.893 3.433 4.087 −1.22053803000 Chr4:63212001- Atp6v1g1 2.452 3.608 1.723 4.240 3.459 −1.00763213000 Chr4:72509001- Aldoart1 2.452 4.193 2.723 4.017 4.000 −1.54872510000 Chr4:83153001- Gm10154 2.452 1.023 4.045 3.017 3.459 −1.00783154000 Chr4:88362001- Klhl9 1.867 3.608 4.531 2.433 3.700 −1.83388363000 Chr5:104534001- Sparcl1 2.867 3.831 3.723 4.017 4.000 −1.133104535000 Chr5:105466001- Gbp8 1.867 4.193 1.723 3.433 3.585 −1.718105467000 Chr5:114456001- Dao 1.867 4.193 1.723 3.754 3.700 −1.833114457000 Chr5:115096001- Trpv4 2.867 3.831 3.723 4.017 3.907 −1.040115097000 Chr5:115131001- Gltp 2.452 3.023 4.531 4.017 3.459 −1.007115132000 Chr5:116469001- Prkab1 1.867 4.608 2.723 4.433 3.322 −1.455116470000 Chr5:117813001- Wsb2 1.867 4.023 3.723 3.433 3.322 −1.455117814000 Chr5:123492001- Morn3 2.452 3.831 3.723 3.754 4.087 −1.635123493000 Chr5:130681001- Rabgef1 2.867 3.608 1.571 4.892 4.170 −1.303130682000 Chr5:139875001- 3110082I17Rik 1.867 3.831 3.723 2.433 3.807−1.940 139876000 Chr5:141212001- Amz1 2.867 4.193 1.571 4.754 3.907−1.040 141213000 Chr5:23883001- Nos3 1.867 3.831 1.723 4.017 3.907−2.040 23884000 Chr5:25007001- 4831440E17Rik 1.867 1.023 3.723 4.2403.907 −2.040 25008000 Chr5:33372001- Ywhah 2.867 3.023 5.045 3.754 4.000−1.133 33373000 Chr5:36063001- Sh3tc1 2.452 3.345 3.308 3.754 4.000−1.548 36064000 Chr5:86518001- Stap1 2.452 3.023 4.045 3.017 4.248−1.796 86519000 Chr5:89861001- Gc 3.452 4.193 5.183 3.433 5.615 −2.16389862000 Chr5:95385001- Gm3176 1.867 4.345 5.045 4.017 3.000 −1.13395386000 Chr6:113425001- Il17rc 2.452 4.483 4.723 4.017 3.907 −1.455113426000 Chr6:113447001- Prrt3 2.452 3.345 3.723 4.017 3.807 −1.355113448000 Chr6:115898001- H1foo 1.867 3.831 4.045 3.017 3.322 −1.455115899000 Chr6:116456001- Olfr212 2.452 3.023 3.723 4.017 3.807 −1.355116457000 Chr6:116574001- Zfp422 3.189 3.345 3.723 5.017 4.248 −1.059116575000 Chr6:120774001- Atp6v1e1 3.452 5.271 5.045 4.017 2.322 1.130120775000 Chr6:125499001- Vwf 1.867 4.023 3.723 1.433 4.000 −2.133125500000 Chr6:135328001- Emp1 3.189 3.023 4.893 3.433 4.322 −1.133135329000 Chr6:30862001- 4930412F09Rik 2.867 4.193 4.308 3.433 4.170−1.303 30863000 Chr6:40146001- Gm5567 2.452 4.193 4.308 2.433 3.459−1.007 40147000 Chr6:40319001- Agk 2.867 3.608 3.308 4.240 4.087 −1.22040320000 Chr6:71803001- Immt 2.867 3.831 3.723 4.017 4.322 −1.45571804000 Chr6:83523001- Stambp 2.452 3.608 3.723 4.240 3.700 −1.24883524000 Chr6:83684001- Vax2 2.452 3.608 4.045 4.433 4.087 −1.63583685000 Chr6:86344001- Pcyox1 1.867 3.608 1.723 3.754 3.170 −1.30386345000 Chr7:100063001- Prcp 3.452 4.023 4.531 4.433 4.644 −1.192100064000 Chr7:106624001- Rps3 2.452 3.831 3.308 4.240 3.459 −1.007106625000 Chr7:108023001- Arhgef17 2.452 3.023 3.723 3.433 4.170 −1.718108024000 Chr7:112892001- Taf10 0.867 2.608 2.723 1.433 3.585 −2.718112893000 Chr7:113577001- Gm4759 1.867 3.345 3.308 4.017 3.459 −1.592113578000 Chr7:117120001- Tmem41b 1.867 3.345 4.308 3.433 3.585 −1.718117121000 Chr7:125259001- Rps15a 0.867 2.023 1.723 2.433 3.459 −2.592125260000 Chr7:135022001- Zfp646 2.867 3.345 4.723 3.433 3.907 −1.040135023000 Chr7:147284001- 1810014F10Rik 2.452 4.023 3.308 4.240 3.459−1.007 147285000 Chr7:148278001- Sigirr 1.867 3.831 3.308 3.017 3.585−1.718 148279000 Chr7:149085001- Tollip 2.452 3.608 2.723 4.017 3.459−1.007 149086000 Chr7:151029001- Dhcr7 2.452 3.831 4.045 3.017 3.807−1.355 151030000 Chr7:25302001- Zfp428 1.867 3.608 3.308 4.017 4.170−2.303 25303000 Chr7:25348001- Xrcc1 2.452 3.023 4.308 3.017 3.459−1.007 25349000 Chr7:28299001- Prx 2.867 3.345 3.308 4.240 3.907 −1.04028300000 Chr7:31429001- Rbm42 2.452 2.023 2.723 4.433 3.459 −1.00731430000 Chr7:3601001- Cnot3 1.867 3.831 4.045 2.433 3.585 −1.7183602000 Chr7:4092001- Leng8 2.452 3.831 4.308 3.017 3.700 −1.248 4093000Chr7:51486001- 1700028J19Rik 3.189 3.608 4.893 4.017 4.248 −1.05951487000 Chr7:51500001- 2410002F23Rik 2.452 4.023 3.308 3.754 3.907−1.455 51501000 Chr7:52246001- Gm15545 2.452 3.608 3.723 3.754 3.700−1.248 52247000 Chr7:52320001- Nosip 2.452 3.608 4.045 3.017 3.585−1.133 52321000 Chr7:52890001- Rasip1 2.867 3.608 4.045 3.754 3.907−1.040 52891000 Chr7:53198001- Ccdc114 2.452 3.023 2.723 4.017 3.585−1.133 53199000 Chr7:5364001- Vmn1r58 2.867 3.345 4.045 4.240 4.087−1.220 5365000 Chr7:63103001- Cyfip1 2.452 3.345 2.723 4.017 3.700−1.248 63104000 Chr7:74884001- Synm 1.867 3.831 3.308 3.017 3.170 −1.30374885000 Chr7:88302001- Slc28a1 1.867 4.023 2.723 3.017 3.459 −1.59288303000 Chr7:97767001- Dlg2 3.452 2.608 4.531 4.433 4.585 −1.13397768000 Chr7:99723001- Ccdc90b 1.867 2.608 4.308 3.017 3.170 −1.30399724000 Chr7:99884001- 4632427E13Rik 1.867 4.193 4.045 4.017 3.807−1.940 99885000 Chr8:107816001- Exoc3l 2.452 2.023 2.723 4.433 3.907−1.455 107817000 Chr8:107932001- Kctd19 2.867 4.345 4.045 4.017 4.087−1.220 107933000 Chr8:108111001- Gm8841 2.867 3.831 4.045 5.339 3.907−1.040 108112000 Chr8:109536001- Sntb2 2.867 3.608 4.045 3.754 4.000−1.133 109537000 Chr8:112200001- 2400003C14Rik 2.452 3.831 3.723 3.7543.807 −1.355 112201000 Chr8:121970001- Osgin1 1.867 2.608 3.308 2.4333.000 −1.133 121971000 Chr8:14902001- Cln8 2.452 3.831 3.308 4.017 3.700−1.248 14903000 Chr8:26697001- Letm2 2.452 4.345 3.723 3.433 4.087−1.635 26698000 Chr8:28157001- Prosc 2.452 3.831 2.723 4.017 3.585−1.133 28158000 Chr8:4106001- Cd209f 1.867 2.608 2.723 4.602 3.322−1.455 4107000 Chr8:47102001- Lrp2bp 3.189 3.831 4.045 4.433 4.585−1.396 47103000 Chr8:4859001- Rpl21-ps14 2.867 3.608 2.723 5.017 4.170−1.303 4860000 Chr8:72236001- Zfp869 0.867 3.608 1.723 2.433 2.807−1.940 72237000 Chr8:72834001- Cope 1.867 4.193 3.723 4.602 3.459 −1.59272835000 Chr8:73056001- Fkbp8 0.715 4.023 4.308 3.754 3.322 −2.60773057000 Chr8:73900001- Ocel1 1.867 4.345 2.723 3.433 3.170 −1.30373901000 Chr8:74708001- Rab8a 2.452 3.831 4.045 3.017 4.000 −1.54874709000 Chr8:83341001- Gab1 1.867 2.608 2.723 3.017 3.170 −1.30383342000 Chr8:86591001- C330011M18Rik 1.867 2.608 3.308 4.433 3.459−1.592 86592000 Chr8:87414001- Gcdh 2.452 3.345 4.308 3.017 3.585 −1.13387415000 Chr8:87613001- Man2b1 0.867 2.608 1.571 4.017 3.700 −2.83387614000 Chr8:97507001- Gpr56 1.867 2.023 3.723 1.433 3.322 −1.45597508000 Chr9:102494001- Cep63 2.867 4.193 3.308 4.433 4.248 −1.381102495000 Chr9:103371001- Bfsp2 2.452 4.023 3.308 3.754 4.170 −1.718103372000 Chr9:107229001- Hemk1 2.452 3.608 4.531 2.433 3.585 −1.133107230000 Chr9:107436001- Tmem115 2.452 3.345 1.723 4.240 3.459 −1.007107437000 Chr9:20294001- Gm17523 1.867 4.345 2.723 3.017 3.807 −1.94020295000 Chr9:21312001- Dnm2 2.452 1.023 4.045 3.017 3.907 −1.45521313000 Chr9:44755001- Ube4a 2.452 4.023 4.045 3.433 3.907 −1.45544756000 Chr9:50447001- Dlat 2.452 4.023 3.308 4.017 3.585 −1.13350448000 Chr9:51674001- 9230115E21Rik 1.867 3.023 3.723 4.017 3.907−2.040 51675000 Chr9:51808001- Gm6981 2.452 2.023 4.045 4.240 4.000−1.548 51809000 Chr9:54478001- Acsbg1 0.867 2.608 2.723 4.602 3.585−2.718 54479000 Chr9:57444001- Ulk3 2.452 3.831 3.308 4.017 3.807 −1.35557445000 Chr9:64030001- Snapc5 1.867 4.023 3.723 4.017 3.000 −1.13364031000 Chr9:78223001- Ooep 1.867 3.023 3.308 4.602 3.459 −1.59278224000 Chr9:96334001- BC043934 2.452 2.023 4.308 3.433 3.807 −1.35596335000 Chr9:97082001- Rpl7a-ps10 1.867 3.345 3.308 3.433 3.807 −1.94097083000 Chr9:98469001- Copb2 2.452 3.831 3.723 3.433 3.907 −1.45598470000 Gene body and promoter cleavage Chr1:13682001- Xkr9 1.867 4.9303.723 3.433 4.392 −2.525 13683000 Chr1:136869001- Ube2t 2.452 3.6084.308 2.433 3.585 −1.133 136870000 Chr1:146094001- Rgs1 1.867 3.8314.045 3.754 4.000 −2.133 146095000 Chr1:157123001- Xpr1 3.452 3.8314.045 4.754 4.644 −1.192 157124000 Chr1:173214001- Usp21 2.452 3.0234.308 2.433 4.392 −1.940 173215000 Chr1:173436001- Refbp2 1.867 3.3453.308 4.433 4.000 −2.133 173437000 Chr1:173826001- Gm10521 1.867 3.8311.723 3.433 4.000 −2.133 173827000 Chr1:174020001- Copa 1.867 3.8313.723 1.433 3.700 −1.833 174021000 Chr1:175530001- Pydc4 2.452 3.6084.308 2.433 3.585 −1.133 175531000 Chr1:180188001- Gm9982 1.867 3.6083.308 3.754 4.087 −2.220 180189000 Chr1:188796001- D1Pas1 2.452 4.0233.723 3.433 3.700 −1.248 188797000 Chr1:190163001- Ush2a 3.867 4.0235.045 4.754 5.170 −1.303 190164000 Chr1:36669001- Fam178b 2.452 3.0233.308 3.754 4.087 −1.635 36670000 Chr1:39422001- Rpl31 2.452 3.831 4.0453.754 3.459 −1.007 39423000 Chr1:4774001- Mrpl15 1.867 2.608 3.308 2.4333.170 −1.303 4775000 Chr1:55232001- Rftn2 2.452 3.608 4.045 3.017 3.700−1.248 55233000 Chr1:58744001- Als2cr12 3.189 4.483 4.308 4.240 4.322−1.133 58745000 Chr1:60784001- Cd28 4.037 4.483 5.424 4.754 5.129 −1.09260785000 Chr1:60951001- Ctla4 1.867 3.608 1.723 3.433 3.807 −1.94060952000 Chr1:64660001- Mettl21a 1.867 3.831 4.045 3.017 4.000 −2.13364661000 Chr1:80380001- Gm6189 2.452 3.023 4.308 3.017 3.459 −1.00780381000 Chr10:105628001- Gm7263 3.452 4.023 4.893 4.754 4.644 −1.192105629000 Chr10:128145001- Pmel 2.867 3.345 4.045 3.754 4.248 −1.381128146000 Chr10:29043001- Echdc1 3.452 3.608 4.531 4.433 4.755 −1.30329044000 Chr10:79634001- Cirbp 2.867 3.023 3.308 4.433 3.907 −1.04079635000 Chr10:80070001- Adat3 0.867 3.608 2.723 3.433 3.000 −2.13380071000 Chr10:80394001- Gadd45b 0.867 3.608 1.723 2.433 2.322 −1.45580395000 Chr10:80437001- Gng7 1.867 3.608 2.723 3.017 3.700 −1.83380438000 Chr10:80738001- Tjp3 1.867 4.023 2.723 3.017 3.170 −1.30380739000 Chr10:86211001- BC030307 2.867 3.831 1.723 4.602 4.248 −1.38186212000 Chr10:98910001- Gad1-ps 1.867 3.023 4.893 3.754 4.459 −2.59298911000 Chr11:106618001- Gm885 0.867 3.831 2.723 3.017 3.700 −2.833106619000 Chr11:115130001- Fdxr 2.452 3.608 3.723 3.433 3.585 −1.133115131000 Chr11:115720001- Myo15b 1.867 3.608 3.308 2.433 3.000 −1.133115721000 Chr11:116534001- 1810032O08Rik 2.867 3.608 4.045 4.433 3.907−1.040 116535000 Chr11:118345001- Engase 1.867 4.023 3.308 3.754 4.170−2.303 118346000 Chr11:119141001- Gaa 2.452 3.831 2.723 4.017 3.807−1.355 119142000 Chr11:120302001- Tspan10 2.452 4.345 1.571 4.433 4.000−1.548 120303000 Chr11:120510001- Gm11768 1.867 3.608 3.723 3.754 3.000−1.133 120511000 Chr11:46057001- Cyfip2 2.867 4.193 3.308 4.240 4.392−1.525 46058000 Chr11:5705001- Pgam2 2.867 3.023 3.308 4.240 3.907−1.040 5706000 Chr11:57987001- Mrpl22 0.867 4.483 4.045 4.240 3.000−2.133 57988000 Chr11:6017001- Nudcd3 1.867 4.023 1.723 3.433 4.000−2.133 6018000 Chr11:60394001- Gm17423 1.867 2.608 2.723 3.017 3.322−1.455 60395000 Chr11:60751001- Map2k3 2.452 3.345 4.308 4.017 4.322−1.870 60752000 Chr11:6427001- Gm11974 2.867 4.023 3.308 4.602 4.087−1.220 6428000 Chr11:6535001- Wap 0.715 3.608 3.308 4.433 4.170 −3.4556536000 Chr11:69712001- 2810408A11Rik 2.452 2.023 5.045 4.433 4.000−1.548 69713000 Chr11:73021001- Shpk 1.867 4.023 3.723 1.433 3.000−1.133 73022000 Chr11:75285001- Tlcd2 1.867 4.023 3.308 4.433 4.170−2.303 75286000 Chr11:80021001- Rhot1 3.452 3.345 4.893 4.017 4.459−1.007 80022000 Chr11:96636001- Snx11 1.867 4.483 3.723 3.433 4.087−2.220 96637000 Chr11:96910001- Mrpl10 2.452 3.608 3.723 3.433 3.700−1.248 96911000 Chr11:98634001- Nr1d1 2.452 3.831 2.723 4.433 3.459−1.007 98635000 Chr12:102142001- Gpr68 2.867 3.345 2.723 4.754 3.907−1.040 102143000 Chr12:102387001- Kif4-ps 2.452 3.831 1.723 4.433 3.459−1.007 102388000 Chr12:114001001- Pld4 1.867 3.023 2.723 3.433 3.322−1.455 114002000 Chr12:4236001- 2410017P09Rik 0.867 2.023 3.308 4.2403.459 −2.592 4237000 Chr12:70398001- Klhdc2 2.452 1.023 3.308 3.7543.807 −1.355 70399000 Chr12:86564001- Eif2b2 1.867 3.345 3.308 3.7543.459 −1.592 86565000 Chr13:101717001- Gm10257 3.452 3.023 5.531 3.7544.954 −1.502 101718000 Chr13:21577001- Zkscan4 2.452 3.023 3.723 3.4333.459 −1.007 21578000 Chr13:21594001- Gm11273 2.452 3.608 3.308 4.0173.585 −1.133 21595000 Chr13:23629001- Hist1h3g 2.867 1.023 3.723 4.4333.907 −1.040 23630000 Chr13:23637001- Hist1h3f 2.452 3.608 4.723 1.4333.459 −1.007 23638000 Chr13:23701001- Hist1h2be 2.452 3.608 4.308 3.0173.907 −1.455 23702000 Chr13:33107001- Serpinb9 2.452 3.608 3.723 4.8923.807 −1.355 33108000 Chr13:40980001- Gcnt2 1.867 3.608 2.723 3.0174.000 −2.133 40981000 Chr13:43463001- Sirt5 2.452 4.345 4.045 3.0173.459 −1.007 43464000 Chr13:58439001- Kif27 2.452 3.345 4.045 3.0173.459 −1.007 58440000 Chr13:62818001- Gm5665 2.867 4.483 4.308 4.4334.170 −1.303 62819000 Chr13:73470001- Mrpl36 1.867 3.345 2.723 3.4333.322 −1.455 73471000 Chr13:76125001- Spata9 2.452 3.023 3.723 3.4333.700 −1.248 76126000 Chr13:76210001- Arsk 2.867 2.608 4.723 3.017 4.459−1.592 76211000 Chr14:118518001- Tgds 1.867 4.345 2.723 4.754 3.322−1.455 118519000 Chr14:26528001- 1700054O19Rik 1.867 4.483 4.045 3.7543.907 −2.040 26529000 Chr14:55505001- Bcl2l2 1.867 3.023 4.308 1.4333.585 −1.718 55506000 Chr14:55721001- Ap1g2 2.452 4.193 4.308 4.0173.585 −1.133 55722000 Chr14:59897001- Phf11 0.867 2.608 1.723 4.6022.585 −1.718 59898000 Chr14:8162001- Gm5797 1.867 3.831 3.308 3.4334.459 −2.592 8163000 Chr15:100241001- Slc11a2 2.867 4.345 3.723 4.0173.907 −1.040 100242000 Chr15:102114001- Mfsd5 2.452 4.930 4.045 3.0173.807 −1.355 102115000 Chr15:38227001- Klf10 3.189 3.831 3.723 4.6022.322 0.867 38228000 Chr15:39584001- Tm7sf4 3.252 3.608 4.045 4.7543.720 −0.468 39585000 Chr15:58819001- Mtss1 2.452 3.345 3.308 3.7543.585 −1.133 58820000 Chr15:61821001- Myc 2.452 4.023 4.045 4.754 3.459−1.007 61822000 Chr15:66430001- Phf20l1 2.867 4.345 4.723 4.433 4.087−1.220 66431000 Chr15:76505001- Ppp1r16a 2.867 3.608 3.723 4.433 4.170−1.303 76506000 Chr15:76883001- Apol6 0.867 4.345 2.723 3.433 3.807−2.940 76884000 Chr15:78243001- Mpst 2.867 4.608 3.723 4.017 4.170−1.303 78244000 Chr15:78984001- Sox10 1.867 3.345 1.723 3.754 3.000−1.133 78985000 Chr15:79977001- Tab1 3.452 3.831 4.531 5.017 4.459−1.007 79978000 Chr15:82842001- Nfam1 2.452 3.831 4.045 3.017 3.700−1.248 82843000 Chr15:89316001- C230037L18Rik 1.867 3.608 3.308 4.0174.322 −2.455 89317000 Chr15:95908001- D030018L15Rik 2.867 4.023 2.7234.433 4.087 −1.220 95909000 Chr15:98548001- Ccdc65 2.867 3.023 4.3083.754 4.392 −1.525 98549000 Chr16:11071001- Snn 2.452 3.608 4.308 3.0174.000 −1.548 11072000 Chr16:11314001- Tnfrsf17 3.189 3.831 4.308 4.2404.322 −1.133 11315000 Chr16:17117001- 2610318N02Rik 2.867 4.193 4.3083.754 4.087 −1.220 17118000 Chr16:18815001- Ufd1l 1.867 3.023 3.7231.433 3.322 −1.455 18816000 Chr16:29585001- Opa1 1.867 4.023 1.723 3.4333.459 −1.592 29586000 Chr16:30524001- Tmem44 2.452 4.483 4.045 3.4333.700 −1.248 30525000 Chr16:32428001- Tctex1d2 2.452 5.023 3.723 3.4333.907 −1.455 32429000 Chr16:38435001- Pla1a 2.867 3.345 1.723 4.8924.000 −1.133 38436000 Chr16:4882001- Fam100a 2.452 3.023 2.723 5.0173.907 −1.455 4883000 Chr16:49788001- Gm15518 2.452 3.831 2.723 4.0174.322 −1.870 49789000 Chr16:50593001- Ccdc54 1.867 4.345 1.571 4.6023.907 −2.040 50594000 Chr16:52249001- Alcam 1.867 3.831 1.571 3.7543.170 −1.303 52250000 Chr16:57064001- 2310005G13Rik 2.452 3.831 4.0453.017 3.459 −1.007 57065000 Chr16:57194001- Tbc1d23 1.867 3.608 1.7233.433 3.170 −1.303 57195000 Chr16:87438001- Rwdd2b 1.867 3.608 3.7233.017 3.170 −1.303 87439000 Chr16:92393001- Rcan1 3.452 3.608 4.0454.754 2.585 0.867 92394000 Chr16:93599001- Setd4 0.867 3.608 2.723 2.4333.459 −2.592 93600000 Chr17:23772001- Mmp25 2.867 2.608 3.723 4.0173.907 −1.040 23773000 Chr17:26107001- Solh 2.452 3.608 4.308 3.017 3.459−1.007 26108000 Chr17:33238001- Zfp563 1.867 3.345 2.723 3.754 3.000−1.133 33239000 Chr17:34201001- Col11a2 1.867 2.608 3.308 3.017 3.807−1.940 34202000 Chr17:34699001- Notch4 1.867 3.608 4.045 2.433 3.907−2.040 34700000 Chr17:35094001- Hspa1b 2.452 3.608 4.531 3.017 3.459−1.007 35095000 Chr17:35887001- Gm20442 2.867 3.345 3.308 4.240 4.087−1.220 35888000 Chr17:45645001- Aars2 2.452 4.831 4.045 4.240 4.000−1.548 45646000 Chr17:6652001- Dynlt1c 2.452 4.345 2.723 4.017 3.700−1.248 6653000 Chr18:33952001- 2410004N09Rik 0.867 3.023 3.308 3.4333.322 −2.455 33953000 Chr18:35865001- 1700066B19Rik 2.452 4.193 4.7234.433 4.322 −1.870 35866000 Chr18:37204001- Pcdha11 3.867 3.345 3.3085.520 4.907 −1.040 37205000 Chr18:38497001- Gnpda1 2.452 2.608 3.3083.754 3.459 −1.007 38498000 Chr18:4377001- Gm17417 2.867 2.608 3.3084.433 4.170 −1.303 4378000 Chr18:61100001- Camk2a 2.452 3.023 4.0453.017 3.907 −1.455 61101000 Chr18:63854001- Txnl1 2.867 4.023 4.5313.017 3.907 −1.040 63855000 Chr19:24753001- E030010A14Rik 2.867 3.0234.308 4.017 4.170 −1.303 24754000 Chr19:24951001- Gm10053 0.867 4.1932.723 4.017 2.322 −1.455 24952000 Chr19:28835001- Gm6788 2.452 3.3452.723 4.433 3.807 −1.355 28836000 Chr19:28958001- Slc1a1 2.867 3.3454.308 3.433 3.907 −1.040 28959000 Chr19:29884001- Ranbp6 2.452 4.4831.723 5.133 4.087 −1.635 29885000 Chr19:4011001- Ndufv1 2.452 3.3454.045 3.433 4.087 −1.635 4012000 Chr19:42201001- Avpi1 2.452 2.023 4.7233.754 3.907 −1.455 42202000 Chr19:4314001- Kdm2a 2.867 4.345 4.045 3.7544.000 −1.133 4315000 Chr19:43900001- Abcc2 2.452 4.193 1.723 4.240 3.459−1.007 43901000 Chr19:44029001- Cpn1 2.452 2.023 4.045 3.017 3.585−1.133 44030000 Chr19:47916001- Wdr96 3.452 3.831 3.723 4.892 4.524−1.072 47917000 Chr19:48010001- Ccdc147 1.867 3.023 2.723 3.017 3.000−1.133 48011000 Chr19:4840001- Ccdc87 2.452 3.023 4.045 3.017 3.907−1.455 4841000 Chr19:4965001- Mrpl11 1.867 4.345 3.723 4.017 4.000−2.133 4966000 Chr19:5091001- Yif1a 1.867 3.831 4.308 3.433 3.585 −1.7185092000 Chr19:60929001- Sfxn4 2.452 3.831 3.308 3.754 3.807 −1.35560930000 Chr19:7012001- Gpr137 1.867 2.608 3.723 3.017 3.807 −1.9407013000 Chr19:7026001- Bad 1.867 3.345 3.308 3.017 3.585 −1.718 7027000Chr19:9053001- Eef1g 1.867 3.345 1.723 3.433 3.907 −2.040 9054000Chr2:112094001- BC125332 1.867 4.345 4.045 3.433 3.170 −1.303 112095000Chr2:120141001- Vps39 2.452 4.193 3.723 3.754 3.807 −1.355 120142000Chr2:128414001- Gm355 2.452 3.608 3.308 4.433 3.700 −1.248 128415000Chr2:129007001- Gm14029 2.452 3.831 4.531 4.433 3.700 −1.248 129008000Chr2:130998001- Spef1 2.452 3.023 3.308 4.602 3.585 −1.133 130999000Chr2:131747001- Prnp 2.867 3.345 3.308 4.433 4.248 −1.381 131748000Chr2:153443001- Commd7 2.867 3.831 4.308 3.754 4.000 −1.133 153444000Chr2:157296001- Src 2.867 3.345 3.723 4.017 3.459 −0.592 157297000Chr2:180192001- Slco4a1 1.867 2.608 3.723 3.017 3.170 −1.303 180193000Chr2:181240001- Tpd52l2 2.452 3.608 3.308 4.240 3.585 −1.133 181241000Chr2:181453001- Oprl1 2.452 3.345 3.723 4.754 3.585 −1.133 181454000Chr2:25489001- Gm13520 2.452 3.608 4.308 3.433 3.700 −1.248 25490000Chr2:25998001- C330006A16Rik 1.867 3.831 3.308 3.433 4.087 −2.22025999000 Chr2:26743001- Surf6 2.867 4.023 4.308 3.433 4.248 −1.38126744000 Chr2:26879001- Slc2a6 2.452 2.023 2.723 4.017 3.907 −1.45526880000 Chr2:29946001- Pkn3 1.867 4.608 3.308 3.017 3.459 −1.59229947000 Chr2:30572001- Gm14488 0.867 2.608 1.571 3.754 2.807 −1.94030573000 Chr2:32432001- Pip5kl1 2.867 3.831 3.723 4.240 4.000 −1.13332433000 Chr2:32482001- Ak1 1.867 2.608 4.045 2.433 3.322 −1.45532483000 Chr2:34717001- Psmd5 2.452 3.608 3.723 3.433 4.907 −2.45534718000 Chr2:38851001- Gm13496 2.452 4.345 2.723 5.017 3.807 −1.35538852000 Chr2:75773001- Ttc30b 2.452 3.345 3.308 4.433 4.000 −1.54875774000 Chr2:76798001- Ttn 3.452 4.023 4.723 4.240 4.858 −1.40676799000 Chr2:93818001- 4921507L20Rik 1.867 4.023 4.308 3.754 4.087−2.220 93819000 Chr3:123274001- Ndst3 2.867 3.608 3.308 4.240 4.087−1.220 123275000 Chr3:142260001- Gbp1 0.867 3.023 4.045 1.433 3.170−2.303 142261000 Chr3:14865001- Car3 0.867 2.023 4.531 2.433 3.170−2.303 14866000 Chr3:32806001- Usp13 1.867 2.608 2.723 3.017 3.000−1.133 32807000 Chr3:33972001- Dnajc19 0.867 3.608 1.571 3.754 2.585−1.718 33973000 Chr4:116793001- Btbd19 1.867 4.023 3.308 3.017 3.170−1.303 116794000 Chr4:124360001- Utp11l 2.452 4.023 4.531 4.017 4.087−1.635 124361000 Chr4:124380001- Fhl3 1.867 4.023 4.308 1.433 3.459−1.592 124381000 Chr4:126805001- Gm12942 1.867 3.831 2.723 4.433 3.000−1.133 126806000 Chr4:128790001- Hpca 1.867 3.831 3.308 2.433 3.170−1.303 128791000 Chr4:129027001- Zbtb8os 2.867 3.831 2.723 4.433 3.907−1.040 129028000 Chr4:132301001- Smpdl3b 1.867 3.608 3.308 2.433 3.700−1.833 132302000 Chr4:135906001- 9130020K20Rik 2.452 3.831 4.045 3.4334.170 −1.718 135907000 Chr4:135912001- Gm17388 2.867 2.608 4.531 3.0174.087 −1.220 135913000 Chr4:138730001- Gm16287 2.452 3.608 3.723 3.7544.000 −1.548 138731000 Chr4:140512001- Gm13031 2.452 2.608 4.045 4.4333.700 −1.248 140513000 Chr4:141180001- Slc25a34 2.452 3.831 3.308 4.0173.459 −1.007 141181000 Chr4:141572001- 4930455G09Rik 1.867 4.345 3.3084.892 3.807 −1.940 141573000 Chr4:143484001- Pramef6 1.867 2.608 3.3082.433 3.585 −1.718 143485000 Chr4:143657001- Pramel4 1.867 5.111 3.7234.017 3.170 −1.303 143658000 Chr4:148533001- Pgd 1.867 3.023 3.308 3.0174.248 −2.381 148534000 Chr4:148856001- Nmnat1 2.867 3.831 4.531 3.4333.907 −1.040 148857000 Chr4:149561001- Car6 0.867 1.023 3.308 1.2804.087 −3.220 149562000 Chr4:151493001- Tnfrsf25 2.452 3.345 4.045 3.7544.000 −1.548 151494000 Chr4:151787001- Kcnab2 2.867 4.023 3.723 4.0174.087 −1.220 151788000 Chr4:154271001- 2810405K02Rik 2.452 3.831 3.3084.602 3.459 −1.007 154272000 Chr4:43459001- Tesk1 2.452 4.023 3.3083.754 3.459 −1.007 43460000 Chr4:43531001- Tpm2 1.867 2.608 3.308 3.7543.459 −1.592 43532000 Chr4:43542001- Tln1 2.867 3.608 3.308 4.240 4.170−1.303 43543000 Chr4:46393001- 5830415F09Rik 1.867 4.193 2.723 4.2403.700 −1.833 46394000 Chr4:48079001- Nr4a3 1.867 4.023 2.723 3.017 3.585−1.718 48080000 Chr4:56757001- Actl7a 1.867 4.483 3.723 3.754 3.807−1.940 56758000 Chr4:89894001- Zfp352 3.189 2.608 4.723 4.240 4.248−1.059 89895000 Chr4:97589001- Nfia 2.867 4.483 4.531 3.017 4.000 −1.13397590000 Chr5:104040001- Slc10a6 2.452 4.345 4.893 4.240 4.170 −1.718104041000 Chr5:105760001- Gbp11 2.452 1.023 4.045 4.017 4.000 −1.548105761000 Chr5:111221001- Ulk1 1.867 2.023 2.723 3.017 3.700 −1.833111222000 Chr5:115544001- Sppl3 2.867 4.483 4.308 3.433 3.907 −1.040115545000 Chr5:117791001- Vsig10 2.867 4.023 4.045 3.754 4.087 −1.220117792000 Chr5:121770001- Gm15800 2.867 3.345 3.723 4.017 3.907 −1.040121771000 Chr5:125044001- Gtf2h3 2.452 3.831 3.308 3.754 3.700 −1.248125045000 Chr5:135658001- Bcl7b 0.867 3.608 3.308 4.017 4.087 −3.220135659000 Chr5:136046001- Ccl24 1.867 4.023 4.308 4.240 3.000 −1.133136047000 Chr5:137871001- Zan 1.867 3.831 1.571 3.754 3.700 −1.833137872000 Chr5:138077001- Lrch4 1.867 4.023 3.308 2.433 3.459 −1.592138078000 Chr5:144095001- 0610040B10Rik 1.867 3.608 3.308 3.433 3.170−1.303 144096000 Chr5:145519001- Tmem130 2.452 3.831 2.723 4.017 3.807−1.355 145520000 Chr5:145947001- Atp5j2 2.452 4.023 2.723 4.754 3.459−1.007 145948000 Chr5:146324001- Cyp3a41b 3.452 4.608 5.183 4.017 4.459−1.007 146325000 Chr5:24094001- Chpf2 2.452 3.608 2.723 4.754 4.322−1.870 24095000 Chr5:34117001- Letm1 2.452 3.831 4.045 3.017 4.087−1.635 34118000 Chr5:38444001- Stx18 2.867 3.023 2.723 4.433 3.907−1.040 38445000 Chr5:44443001- Prom1 1.867 3.608 3.308 2.433 3.585−1.718 44444000 Chr5:73720001- Ociad2 2.452 3.831 2.723 4.754 3.459−1.007 73721000 Chr5:76348001- Kdr 2.452 3.831 1.723 4.240 3.807 −1.35576349000 Chr5:87087001- Tmprss11bnl 2.867 2.023 3.308 4.433 4.087 −1.22087088000 Chr6:113015001- Thumpd3 2.867 3.608 3.723 4.892 4.000 −1.133113016000 Chr6:122882001- Clec4a1 0.715 3.608 3.308 3.754 3.807 −3.092122883000 Chr6:123007001- Clec4b1 2.452 3.608 4.045 4.017 3.807 −1.355123008000 Chr6:126779001- Ndufa9 2.452 4.345 1.723 4.240 3.807 −1.355126780000 Chr6:136707001- Gucy2c 2.452 3.831 4.531 1.433 4.644 −2.192136708000 Chr6:13905001- 1110019D14Rik 3.452 4.483 4.308 4.602 4.524−1.072 13906000 Chr6:145083001- Lrmp 1.867 2.608 2.723 3.017 3.170−1.303 145084000 Chr6:147023001- Gm5887 2.452 4.023 4.045 3.433 3.459−1.007 147024000 Chr6:29242001- Fam71f2 2.452 4.023 3.308 5.433 3.459−1.007 29243000 Chr6:49025001- 2410003K15Rik 2.867 3.831 4.308 3.7544.248 −1.381 49026000 Chr6:72375001- Ggcx 2.452 4.483 2.723 4.433 3.585−1.133 72376000 Chr6:83432001- Dguok 1.867 4.345 1.723 3.433 4.000−2.133 83433000 Chr6:84528001- Cyp26b1 2.452 3.608 4.045 3.433 3.700−1.248 84529000 Chr6:86330001- Snrpg 2.867 3.023 4.045 4.892 3.907−1.040 86331000 Chr6:89133001- Gm6507 1.867 3.608 3.723 4.017 3.459−1.592 89134000 Chr7:100184001- Gm16744 2.452 3.608 3.308 3.754 3.907−1.455 100185000 Chr7:104485001- Kctd21 1.867 3.831 3.308 3.433 3.170−1.303 104486000 Chr7:108003001- Relt 2.867 3.831 4.308 3.754 3.907−1.040 108004000 Chr7:110567001- Usp17l5 0.867 3.608 4.045 4.017 2.322−1.455 110568000 Chr7:112704001- Smpd1 0.867 3.831 4.045 4.017 2.585−1.718 112705000 Chr7:11752001- Zscan4d 1.867 3.608 2.723 4.433 3.000−1.133 11753000 Chr7:123239001- 1110004F10Rik 0.867 4.023 4.723 4.6023.585 −2.718 123240000 Chr7:128161001- Gm9234 1.867 4.193 3.308 3.7543.700 −1.833 128162000 Chr7:129300001- Gm15489 1.867 4.345 3.308 3.7543.000 −1.133 129301000 Chr7:133554001- Cd19 2.867 3.345 4.045 3.7543.907 −1.040 133555000 Chr7:134121001- Cdipt 2.867 4.930 4.045 4.4333.907 −1.040 134122000 Chr7:135045001- Bckdk 0.867 4.023 3.308 4.0173.907 −3.040 135046000 Chr7:135079001- Prss36 1.867 2.608 1.23 3.4333.459 −1.592 135080000 Chr7:147309001- Paox 2.452 3.831 3.723 4.0174.000 −1.548 147310000 Chr7:148036001- Odf3 1.867 4.608 1.723 4.4333.700 −1.833 148037000 Chr7:148133001- Athl1 2.452 3.608 4.531 3.4333.585 −1.133 148134000 Chr7:16808001- Dhx34 1.867 3.345 3.723 1.4333.907 −2.040 16809000 Chr7:17327001- Ap2s1 1.867 4.345 4.308 3.754 4.000−2.133 17328000 Chr7:20091001- Bloc1s3 2.452 2.608 4.045 3.017 4.087−1.635 20092000 Chr7:25381001- Ethe1 3.452 4.023 3.308 5.017 4.524−1.072 25382000 Chr7:26144001- Megf8 2.452 2.608 3.723 3.433 3.459−1.007 26145000 Chr7:27982001- BC024978 1.867 2.023 2.723 3.017 3.459−1.592 27983000 Chr7:29086001- Dll3 1.867 3.345 3.308 4.433 3.459 −1.59229087000 Chr7:31892001- Hpn 2.452 4.023 1.571 4.433 3.585 −1.13331893000 Chr7:4086001- Ttyh1 0.867 3.608 3.723 2.433 3.170 −2.3034087000 Chr7:4579001- Tmem86b 2.867 4.724 4.045 4.240 4.000 −1.1334580000 Chr7:4696001- Suv420h2 2.452 4.023 3.308 4.602 3.459 −1.0074697000 Chr7:50609001- Siglec5 2.867 3.345 2.723 4.433 3.907 −1.04050610000 Chr7:50706001- Etfb 2.452 4.193 3.723 3.433 3.459 −1.00750707000 Chr7:52032001- Vrk3 2.452 1.023 2.723 4.017 3.585 −1.13352033000 Chr7:52229001- Cpt1c 2.867 3.831 4.045 3.754 3.907 −1.04052230000 Chr7:71486001- Gm20457 1.867 4.193 3.308 3.433 3.807 −1.94071487000 Chr7:7243001- Clcn4-2 1.867 4.193 3.723 2.433 3.807 −1.9407244000 Chr7:86061001- Isg20 2.452 2.023 4.045 3.754 3.700 −1.24886062000 Chr7:86270001- Hapln3 1.867 4.831 2.723 3.754 3.322 −1.45586271000 Chr7:86529001- Rlbp1 2.452 3.345 3.723 3.433 3.907 −1.45586530000 Chr8:109919001- Nqo1 2.452 4.023 4.045 3.433 3.907 −1.455109920000 Chr8:12873001- Gm15347 1.867 3.023 3.308 2.433 3.322 −1.45512874000 Chr8:15039001- BB014433 2.867 3.345 3.723 4.240 3.907 −1.04015040000 Chr8:54598001- Aga 1.867 2.608 4.045 3.754 4.087 −2.22054599000 Chr8:72279001- Gm20422 1.867 2.608 2.723 3.017 4.000 −2.13372280000 Chr8:72428001- Tssk6 0.867 3.345 2.723 1.433 3.459 −2.59272429000 Chr8:72857001- Upf1 1.867 4.193 3.308 2.433 3.459 −1.59272858000 Chr8:72895001- Comp 1.867 4.023 2.723 4.017 3.700 −1.83372896000 Chr8:73361001- Arrdc2 2.452 4.483 4.045 3.433 4.170 −1.71873362000 Chr8:74438001- Zfp882 2.452 4.193 3.723 4.240 3.459 −1.00774439000 Chr8:74716001- Hsh2d 2.867 2.023 3.723 4.433 3.907 −1.04074717000 Chr8:97646001- Kifc3 2.452 4.193 2.723 4.017 3.907 −1.45597647000 Chr8:98232001- Ndrg4 2.452 3.608 3.308 3.754 3.907 −1.45598233000 Chr9:100893001- Pccb 2.867 3.608 4.308 3.433 4.248 −1.381100894000 Chr9:106089001- Wdr82 2.452 4.023 1.723 4.240 3.907 −1.455106090000 Chr9:106371001- Parp3 2.452 3.831 3.308 3.754 3.459 −1.007106372000 Chr9:107456001- Rassf1 2.452 2.023 4.531 2.433 3.700 −1.248107457000 Chr9:107833001- 4921517D21Rik 2.452 3.608 3.723 3.433 3.585−1.133 107834000 Chr9:110522001- Nradd 2.452 4.345 4.308 3.017 3.459−1.007 110523000 Chr9:110627001- Pth1r 1.867 4.023 2.723 3.017 3.322−1.455 110628000 Chr9:119056001- Dlec1 1.867 2.608 1.723 3.433 3.000−1.133 119057000 Chr9:122809001- A530083I20Rik 2.452 3.345 2.723 4.0173.459 −1.007 122810000 Chr9:15041001- 2200002K05Rik 0.867 4.023 3.7234.240 3.000 −2.133 15042000 Chr9:20148001- Zfp560 1.867 3.608 4.0451.280 3.000 −1.133 20149000 Chr9:44331001- Cxcr5 2.452 2.608 3.723 4.2403.907 −1.455 44332000 Chr9:50331001- Pts 2.452 3.831 2.723 5.240 3.700−1.248 50332000 Chr9:58058001- 1600029O15Rik 1.867 3.345 1.723 3.7543.807 −1.940 58059000 Chr9:61217001- Gm10655 2.452 3.023 4.045 3.0173.700 −1.248 61218000 Chr9:61912001- Glce 2.452 3.023 3.723 3.754 4.248−1.796 61913000 Chr9:63485001- Aagab 2.452 3.023 3.308 4.017 3.459−1.007 63486000 Chr9:63968001- Lctl 1.867 4.345 3.308 3.017 3.807 −1.94063969000 Chr9:64184001- Dis3l 2.867 4.023 4.308 3.754 3.907 −1.04064185000 Chr9:98499001- Mrps22 2.452 4.608 2.723 4.754 3.907 −1.45598500000 ChrX:103772001- Cysltr1 1.867 3.608 4.045 1.280 3.000 −1.133103773000 Gene body cleavage Chr1:107175001- Rnf152 1.867 3.023 1.7233.433 3.459 −1.592 107176000 Chr1:107691001- Tnfrsf11a 2.867 4.193 4.3083.433 3.322 −0.455 107692000 Chr1:129673001- Ccnt2 1.867 3.831 2.7233.017 3.585 −1.718 129674000 Chr1:133565001- Ctse 2.452 4.023 3.3083.754 4.000 −1.548 133566000 Chr1:134032001- Cdk18 0.715 3.831 2.7232.433 3.459 −2.744 134033000 Chr1:141450001- Cfhr1 1.867 3.023 4.3084.240 3.585 −1.718 141451000 Chr1:141645001- Gm4788 3.189 3.023 4.0454.433 4.858 −1.669 141646000 Chr1:153298001- 1190005F20Rik 1.867 4.3454.045 1.433 3.807 −1.940 153299000 Chr1:172231001- Gm7694 2.452 3.3453.308 3.754 3.807 −1.355 172232000 Chr1:173224001- Ufc1 1.867 4.4833.723 4.433 3.170 −1.303 173225000 Chr1:174416001- Igsf9 0.867 2.6083.308 3.017 3.170 −2.303 174417000 Chr1:21064001- Tram2 1.867 2.6081.723 3.433 3.585 −1.718 21065000 Chr1:34644001- Fam123c 2.452 2.6082.723 4.017 3.459 −1.007 34645000 Chr1:53002001- 1700019D03Rik 3.8674.023 5.424 4.240 4.954 −1.087 53003000 Chr1:58000001- Spats2l 1.8674.345 3.308 2.433 4.170 −2.303 58001000 Chr1:58990001- Trak2 3.452 4.4834.045 4.754 5.129 −1.677 58991000 Chr1:74999001- Ihh 2.867 3.831 4.0454.017 4.170 −1.303 75000000 Chr1:75236001- Dnajb2 1.867 4.345 4.7233.017 3.700 −1.833 75237000 Chr1:75398001- Speg 1.867 3.831 2.723 3.0173.700 −1.833 75399000 Chr1:87793001- Itm2c 2.452 4.193 2.723 4.433 3.459−1.007 87794000 Chr1:87834001- 4933407L21Rik 2.452 3.608 3.308 3.7543.807 −1.355 87835000 Chr1:94805001- Dusp28 1.867 4.023 3.723 4.4333.000 −1.133 94806000 Chr1:95739001- D2hgdh 2.867 4.023 4.531 4.0174.907 −2.040 95740000 Chr10:103615001- Gm6763 0.867 2.023 2.723 3.0173.322 −2.455 103616000 Chr10:111631001- Caps2 2.452 4.345 3.308 3.7544.000 −1.548 111632000 Chr10:114787001- Tmem19 1.867 3.608 4.045 4.2404.087 −2.220 114788000 Chr10:119581001- Irak3 1.867 3.608 3.723 1.4333.459 −1.592 119582000 Chr10:126635001- F420014N23Rik 2.452 3.608 2.7234.017 3.585 −1.133 126636000 Chr10:126683001- Kif5a 2.867 3.023 3.3084.240 3.907 −1.040 126684000 Chr10:128061001- Rps26 2.452 4.483 3.3083.754 3.807 −1.355 128062000 Chr10:128113001- Rab5b 2.452 4.345 4.0453.754 3.459 −1.007 128114000 Chr10:13219001- Fuca2 1.867 3.831 1.7234.017 3.170 −1.303 13220000 Chr10:34003001- Tspyl1 2.452 3.345 3.7233.754 3.700 −1.248 34004000 Chr10:42409001- Ostm1 3.452 3.345 4.0454.754 3.907 −0.455 42410000 Chr10:43669001- Aim1 1.867 4.023 2.723 3.0173.585 −1.718 43670000 Chr10:52153001- Nus1 2.452 4.345 4.045 3.433 3.459−1.007 52154000 Chr10:59184001- Cbara1 2.867 4.483 3.723 4.017 3.907−1.040 59185000 Chr10:70798001- Cisd1 1.867 3.345 1.571 4.017 3.170−1.303 70799000 Chr10:75244001- Gstt3 1.867 3.345 3.308 3.433 3.170−1.303 75245000 Chr10:77661001- Trappc10 2.867 3.608 4.045 3.754 3.907−1.040 77662000 Chr10:78995001- Ppap2c 0.867 1.023 1.723 3.017 3.170−2.303 78996000 Chr10:79382001- Kiss1r 1.867 3.023 2.723 3.433 3.807−1.940 79383000 Chr10:79497001- Polr2e 1.867 4.023 4.045 3.017 3.459−1.592 79498000 Chr10:79757001- Rps15 2.452 3.831 4.045 3.017 3.807−1.355 79758000 Chr10:79850001- Mex3d 0.867 3.023 1.723 3.754 2.807−1.940 79851000 Chr10:80049001- Fam108a 1.867 4.345 4.893 3.433 3.170−1.303 80050000 Chr10:80496001- Slc39a3 1.867 2.608 4.045 4.433 3.170−1.303 80497000 Chr10:80609001- Zbtb7a 1.867 3.023 4.045 2.433 3.000−1.133 80610000 Chr10:81002001- Gna11 1.867 4.023 1.723 3.754 3.170−1.303 81003000 Chr10:81155001- Gm8112 1.867 2.608 2.723 3.017 3.000−1.133 81156000 Chr10:93604001- Fgd6 3.189 3.831 4.045 4.433 4.322−1.133 93605000 Chr11:100555001- Gm11547 2.452 4.193 2.723 4.017 4.000−1.548 100556000 Chr11:100684001- Stat5b 2.452 3.345 3.723 3.433 4.248−1.796 100685000 Chr11:101030001- Plekhh3 2.452 1.023 4.045 3.017 3.585−1.133 101031000 Chr11:102084001- Hdac5 2.867 3.608 3.723 4.017 3.907−1.040 102085000 Chr11:102145001- Tmub2 3.452 3.345 4.308 4.754 4.459−1.007 102146000 Chr11:102981001- Hexim1 2.452 3.831 2.723 4.017 4.000−1.548 102982000 Chr11:104458001- Myl4 1.867 3.608 4.045 1.433 4.000−2.133 104459000 Chr11:105884001- Kcnh6 2.867 3.831 4.308 3.433 3.907−1.040 105885000 Chr11:106196001- Scn4a 2.452 4.345 3.308 3.754 3.700−1.248 106197000 Chr11:107482001- Helz 3.189 3.608 4.531 4.017 4.644−1.455 107483000 Chr11:109449001- Wipi1 2.452 3.023 3.723 3.433 3.700−1.248 109450000 Chr11:110261001- Map2k6 2.867 3.023 4.893 1.433 3.270−0.403 110262000 Chr11:115469001- Mrps7 1.867 3.023 3.723 3.433 3.322−1.455 115470000 Chr11:116155001- Exoc7 1.867 3.345 4.045 3.433 3.322−1.455 116156000 Chr11:116394001- Sphk1 1.867 2.608 1.723 4.017 3.322−1.455 116395000 Chr11:117477001- 2900041M22Rik 1.867 4.023 4.045 3.7543.000 −1.133 117478000 Chr11:117670001- Syngr2 1.867 3.345 1.723 4.4333.459 −1.592 117671000 Chr11:118033001- Cyth1 1.867 4.345 1.571 3.7543.585 −1.718 118034000 Chr11:118899001- Cbx8 0.867 4.023 3.723 4.4333.459 −2.592 118900000 Chr11:120210001- 0610009L18Rik 1.867 3.608 3.3082.433 3.000 −1.133 120211000 Chr11:120352001- Gm11788 1.867 2.608 2.7233.017 3.322 −1.455 120353000 Chr11:120410001- Fam195b 1.867 4.193 3.3083.433 3.585 −1.718 120411000 Chr11:120474001- Pcyt2 1.867 2.608 1.7233.754 3.000 −1.133 120475000 Chr11:20101001- Rab1 1.867 3.345 1.7233.433 3.585 −1.718 20102000 Chr11:21903001- Otx1 2.452 3.345 3.308 3.7543.700 −1.248 21904000 Chr11:3202001- Patz1 2.867 2.023 4.531 4.240 3.907−1.040 3203000 Chr11:3823001- Tcn2 2.452 4.023 3.308 3.754 3.807 −1.3553824000 Chr11:3991001- Mtfp1 1.867 4.193 3.723 3.754 3.700 −1.8333992000 Chr11:3996001- Sec14l2 2.452 3.608 4.531 2.433 3.585 −1.1333997000 Chr11:4171001- Lif 1.867 2.023 3.723 1.433 4.000 −2.133 4172000Chr11:4644001- Cabp7 2.452 4.483 4.308 3.017 3.585 −1.133 4645000Chr11:51432001- Nhp2 1.867 3.831 3.308 3.017 3.585 −1.718 51433000Chr11:51459001- N4bp3 2.452 5.023 4.045 4.433 3.907 −1.455 51460000Chr11:53431001- Il4 1.867 1.023 3.308 3.433 3.585 −1.718 53432000Chr11:5768001- Aebp1 2.867 4.193 4.531 3.017 3.907 −1.040 5769000Chr11:58972001- A230051G13Rik 0.867 3.345 3.723 3.433 3.585 −2.71858973000 Chr11:59022001- 2310033P09Rik 1.867 3.345 4.045 1.433 3.170−1.303 59023000 Chr11:59144001- Wnt9a 1.867 3.345 1.723 3.433 3.907−2.040 59145000 Chr11:59475001- Mprip 1.867 3.608 3.723 1.433 3.459−1.592 59476000 Chr11:59603001- Flcn 2.867 3.608 4.308 3.433 4.248−1.381 59604000 Chr11:61307001- Mapk7 0.867 1.023 2.723 3.754 2.322−1.455 61308000 Chr11:62090001- Zswim7 1.867 4.483 3.723 3.433 3.459−1.592 62091000 Chr11:6492001- Ccm2 3.189 3.345 3.723 4.602 4.524 −1.3356493000 Chr11:66842001- Tmem220 1.867 3.608 4.045 4.017 3.459 −1.59266843000 Chr11:67777001- Wdr16 2.452 4.345 2.723 4.017 3.700 −1.24867778000 Chr11:68902001- Vamp2 1.867 0.871 2.723 3.433 3.322 −1.45568903000 Chr11:69171001- Chd3 1.867 3.345 3.723 1.433 3.585 −1.71869172000 Chr11:69630001- 4933402P03Rik 2.452 3.608 4.045 3.433 3.585−1.133 69631000 Chr11:69756001- Slc2a4 0.867 3.608 3.308 1.280 3.459−2.592 69757000 Chr11:70052001- Rnasek 1.867 3.023 4.893 4.240 3.000−1.133 70053000 Chr11:70707001- Rabep1 2.867 4.608 3.723 4.017 4.170−1.303 70708000 Chr11:72212001- Smtnl2 1.867 2.608 2.723 3.017 3.170−1.303 72213000 Chr11:72248001- Ggt6 2.452 3.345 2.723 4.240 3.585−1.133 72249000 Chr11:74449001- E130309D14Rik 2.452 4.345 3.723 3.7543.807 −1.355 74450000 Chr11:78003001- Rab34 1.867 3.023 4.045 3.7544.170 −2.303 78004000 Chr11:78138001- Aldoc 2.452 4.023 3.723 3.7544.087 −1.635 78139000 Chr11:79965001- Adap2 2.867 3.831 2.723 4.6024.000 −1.133 79966000 Chr11:82832001- Slfn8 2.867 3.608 4.308 3.4333.907 −1.040 82833000 Chr11:94642001- Tmem92-ps 2.452 3.608 3.308 4.2403.700 −1.248 94643000 Chr11:95007001- Dlx4 2.452 2.608 1.723 4.240 3.459−1.007 95008000 Chr11:95130001- Tac4 2.452 4.193 4.531 4.017 3.907−1.455 95131000 Chr11:96144001- Hoxb8 0.867 3.023 3.308 2.433 2.807−1.940 96145000 Chr11:97885001- Gm11629 2.867 3.831 3.308 4.240 4.000−1.133 97886000 Chr11:98218001- Ppp1r1b 2.452 3.345 2.723 4.017 3.700−1.248 98219000 Chr12:102323001- D130020L05Rik 1.867 3.345 2.723 3.4333.585 −1.718 102324000 Chr12:110854001- Rian 1.867 3.345 3.308 3.0173.700 −1.833 110855000 Chr12:111764001- Ppp2r5c 2.867 3.023 4.308 3.4333.907 −1.040 111765000 Chr12:112812001- 2810029C07Rik 1.867 2.608 4.0452.433 3.807 −1.940 112813000 Chr12:112946001- Bag5 2.452 1.023 3.3083.754 3.907 −1.455 112947000 Chr12:113921001- Zbtb42 0.867 3.345 1.7233.017 3.000 −2.133 113922000 Chr12:114178001- Nudt14 1.867 4.193 4.0453.017 3.322 −1.455 114179000 Chr12:114279001- Pacs2 2.867 4.193 3.3084.240 3.907 −1.040 114280000 Chr12:114383001- Crip2 1.867 3.831 2.7233.433 3.459 −1.592 114384000 Chr12:25178001- Gm16372 1.867 3.831 1.7234.433 3.459 −1.592 25179000 Chr12:25670001- Kidins220 2.867 2.608 4.5313.017 3.907 −1.040 25671000 Chr12:25782001- Id2 1.867 3.345 4.045 2.4333.000 −1.133 25783000 Chr12:36911001- Ankmy2 2.867 2.023 2.723 4.4334.000 −1.133 36912000 Chr12:45585001- Nrcam 3.452 4.023 4.723 4.2404.459 −1.007 45586000 Chr12:71068001- Gm3086 2.452 4.193 3.308 4.8924.087 −1.635 71069000 Chr12:80245001- Arg2 3.189 3.345 4.308 4.433 4.459−1.270 80246000 Chr12:80271001- Vti1b 2.867 3.831 3.308 5.017 4.087−1.220 80272000 Chr12:81230001- 2310015A10Rik 2.452 4.023 4.045 3.0173.585 −1.133 81231000 Chr13:102470001- Pik3r1 3.189 4.023 4.723 4.0173.585 −0.396 102471000 Chr13:103498001- Cd180 1.867 4.193 2.723 3.0173.807 −1.940 103499000 Chr13:21923001- Hist1h4n 1.867 3.831 3.308 3.7543.000 −1.133 21924000 Chr13:23858001- Hist1h1a 2.452 2.608 3.308 3.7543.585 −1.133 23859000 Chr13:33416001- Serpinb9f 1.867 3.608 2.723 3.4333.807 −1.940 33417000 Chr13:35011001- 1700026J04Rik 0.715 3.608 4.7231.280 3.322 −2.607 35012000 Chr13:43635001- Ccdc90a 1.867 2.608 3.3083.433 3.459 −1.592 43636000 Chr13:45501001- Mylip 2.867 3.345 4.0454.017 4.000 −1.133 45502000 Chr13:46061001- 5033430I15Rik 0.867 3.6083.308 4.017 2.585 −1.718 46062000 Chr13:53063001- Nfil3 1.867 3.3452.723 3.433 4.000 −2.133 53064000 Chr13:54483001- Cplx2 1.867 1.0231.723 3.433 3.000 −1.133 54484000 Chr13:54797001- Rnf44 2.867 4.0234.045 4.017 3.907 −1.040 54798000 Chr13:54826001- Cdhr2 2.452 3.3454.308 2.433 3.907 −1.455 54827000 Chr13:59755001- Golm1 1.867 4.0234.045 3.754 3.700 −1.833 59756000 Chr13:62318001- Gm17352 2.452 3.8314.531 3.433 3.807 −1.355 62319000 Chr13:74176001- Cep72 2.452 4.3452.723 4.433 3.585 −1.133 74177000 Chr13:9110001- Larp4b 4.567 5.0235.630 5.520 6.209 −1.642 9111000 Chr14:120903001- Rap2a 1.867 3.8312.723 3.754 3.700 −1.833 120904000 Chr14:21132001- Nudt13 2.867 3.8313.723 4.017 4.170 −1.303 21133000 Chr14:25312001- Rps24 2.452 4.6081.723 4.433 3.700 −1.248 25313000 Chr14:26280001- D930049A15Rik 0.8673.345 2.723 3.433 2.807 −1.940 26281000 Chr14:26695001- Anxa11 0.7152.608 1.571 3.017 2.000 −1.285 26696000 Chr14:32906001- Oxnad1 2.4522.023 3.723 3.433 3.459 −1.007 32907000 Chr14:35128001- Glud1 2.4523.608 1.723 4.433 3.585 −1.133 35129000 Chr14:35367001- Ldb3 2.867 4.1934.531 3.433 4.248 −1.381 35368000 Chr14:48699001- Gm6055 0.867 4.6083.308 4.433 3.585 −2.718 48700000 Chr14:52529001- Ndrg2 2.452 3.8313.308 3.754 4.000 −1.548 52530000 Chr14:54857001- Dad1 1.867 3.023 2.7233.433 3.170 −1.303 54858000 Chr14:54983001- Oxa1l 2.452 3.023 2.7234.433 3.585 −1.133 54984000 Chr14:55233001- Psmb5 2.452 4.345 3.3084.240 3.700 −1.248 55234000 Chr14:56280001- Nedd8 2.452 3.023 4.5314.240 3.700 −1.248 56281000 Chr14:58448001- Mrp63 1.867 3.608 3.3084.240 3.585 −1.718 58449000 Chr14:73922001- Nudt15 2.452 3.608 3.3084.017 3.700 −1.248 73923000 Chr15:100958001- Acvrl1 2.452 3.023 2.7234.240 4.087 −1.635 100959000 Chr15:102983001- Smug1 2.867 3.608 4.0453.754 4.000 −1.133 102984000 Chr15:6559001- Fyb 2.867 3.831 3.308 4.2403.907 −1.040 6560000 Chr15:66816001- Gm2895 2.452 1.023 2.723 4.0173.907 −1.455 66817000 Chr15:74409001- Bai1 2.452 3.345 3.723 3.433 3.700−1.248 74410000 Chr15:74503001- Arc 2.452 4.023 3.308 3.754 3.807 −1.35574504000 Chr15:76174001- Cyc1 0.867 3.023 2.723 4.240 2.807 −1.94076175000 Chr15:76364001- Fbxl6 0.867 2.023 1.723 3.433 2.322 −1.45576365000 Chr15:78387001- Rac2 2.452 4.193 1.723 4.240 3.807 −1.35578388000 Chr15:78818001- Triobp 2.867 2.608 3.723 4.017 4.170 −1.30378819000 Chr15:79555001- Sun2 1.867 3.345 2.723 3.017 3.000 −1.13379556000 Chr15:80077001- Smcr7l 2.867 3.608 3.308 4.433 4.087 −1.22080078000 Chr15:82168001- Naga 1.867 3.345 3.308 3.433 3.170 −1.30382169000 Chr15:83416001- Ttll12 2.867 3.831 4.531 4.433 4.087 −1.22083417000 Chr15:85403001- Wnt7b 1.867 3.831 2.723 3.017 3.170 −1.30385404000 Chr15:97727001- Vdr 1.867 3.345 1.723 3.433 3.322 −1.45597728000 Chr15:99222001- Tmbim6 1.867 4.724 3.308 4.240 3.170 −1.30399223000 Chr15:99335001- Faim2 1.867 3.345 3.308 4.017 3.322 −1.45599336000 Chr15:99544001- Smarcd1 2.452 4.193 3.723 3.754 4.000 −1.54899545000 Chr16:18423001- Comt 2.867 4.023 3.723 4.433 4.087 −1.22018424000 Chr16:32161001- Lrrc33 2.867 3.831 4.531 3.017 3.907 −1.04032162000 Chr16:38574001- Tmem39a 2.452 4.345 3.723 3.754 3.459 −1.00738575000 Chr16:45119001- Ccdc80 2.867 2.608 4.045 3.754 4.087 −1.22045120000 Chr16:4624001- Glis2 2.867 4.608 4.045 4.017 3.907 −1.0404625000 Chr16:4698001- Dnaja3 2.867 4.930 3.308 4.240 4.170 −1.3034699000 Chr16:49800001- Gm16619 2.452 3.608 3.723 3.754 3.459 −1.00749801000 Chr16:52029001- Cblb 3.452 4.193 4.893 4.017 4.000 −0.54852030000 Chr16:70373001- Gbe1 2.867 3.608 4.893 1.433 4.807 −1.94070374000 Chr16:8635001- Tmem186 2.452 3.345 4.723 3.754 3.459 −1.0078636000 Chr16:93682001- Cbr3 2.452 2.608 3.723 4.433 3.807 −1.35593683000 Chr16:95933001- Ets2 1.867 3.023 4.045 3.017 3.170 −1.30395934000 Chr16:96428001- Sh3bgr 2.867 4.193 4.045 4.240 3.907 −1.04096429000 Chr17:24826001- Syngr3 0.715 3.345 4.531 3.017 2.322 −1.60724827000 Chr17:33074001- Cyp4f13 2.452 3.608 3.308 3.754 3.459 −1.00733075000 Chr17:34046001- BC051226 1.867 1.023 3.308 2.433 3.585 −1.71834047000 Chr17:34087001- B3galt4 1.867 3.345 3.723 1.433 3.700 −1.83334088000 Chr17:34104001- Vps52 2.452 4.345 3.723 4.754 3.459 −1.00734105000 Chr17:34449001- H2-Eb1 1.867 3.831 1.723 3.433 3.322 −1.45534450000 Chr17:34865001- C4b 2.867 3.023 3.723 4.017 4.087 −1.22034866000 Chr17:35164001- Ng23 0.867 3.023 1.571 3.754 3.807 −2.94035165000 Chr17:35331001- Ltb 1.867 2.023 3.308 3.017 3.170 −1.30335332000 Chr17:36598001- H2-M10.4 1.867 3.023 2.723 3.754 3.700 −1.83336599000 Chr17:47577001- AI661453 2.452 3.831 4.531 2.433 3.459 −1.00747578000 Chr17:56929001- Rfx2 1.867 3.023 2.723 3.017 3.585 −1.71856930000 Chr17:57200001- Crb3 2.452 3.831 4.045 4.017 3.807 −1.35557201000 Chr18:35023001- Egr1 2.452 3.608 4.531 3.433 3.459 −1.00735024000 Chr18:36127001- Psd2 1.867 3.608 1.723 3.433 3.807 −1.94036128000 Chr18:39542001- Gm15337 2.452 3.345 3.308 3.754 3.807 −1.35539543000 Chr18:43476001- Stk32a 1.867 4.023 3.308 2.433 3.170 −1.30343477000 Chr18:4668001- 9430020K01Rik 1.867 3.023 1.723 3.433 3.000−1.133 4669000 Chr18:48206001- Gm5506 2.452 4.193 2.723 4.017 3.700−1.248 48207000 Chr18:54144001- Gm5507 2.452 3.345 4.045 4.892 4.000−1.548 54145000 Chr18:60728001- Rbm22 2.452 4.023 4.045 3.433 3.585−1.133 60729000 Chr18:61210001- Pdgfrb 1.867 3.023 1.571 3.754 3.459−1.592 61211000 Chr18:67485001- B430212C06Rik 2.452 3.023 1.571 4.4334.170 −1.718 67486000 Chr18:70178001- Rab27b 1.867 3.023 2.723 3.0173.459 −1.592 70179000 Chr18:75120001- Lipg 2.452 4.023 4.045 3.754 3.459−1.007 75121000 Chr18:75162001- Rpl17 2.867 4.483 4.531 3.017 4.087−1.220 75163000 Chr19:21346001- Zfand5 0.867 2.608 2.723 3.433 2.585−1.718 21347000 Chr19:24416001- Pip5k1b 1.867 2.608 1.723 3.433 4.000−2.133 24417000 Chr19:29031001- 4430402I18Rik 2.452 3.023 4.308 2.4333.807 −1.355 29032000 Chr19:3899001- Tcirg1 2.452 4.345 3.308 3.7544.000 −1.548 3900000 Chr19:4171001- Carns1 1.867 3.831 1.723 3.433 3.585−1.718 4172000 Chr19:4195001- Ppp1ca 2.452 4.023 4.045 3.017 4.585−2.133 4196000 Chr19:45065001- Sema4g 2.452 3.831 2.723 4.017 4.000−1.548 45066000 Chr19:45093001- Lzts2 1.867 3.023 3.308 3.754 3.459−1.592 45094000 Chr19:46402001- Fbxl15 2.867 4.023 2.723 4.602 3.907−1.040 46403000 Chr19:46743001- Cyp17a1 1.867 3.345 2.723 3.754 3.585−1.718 46744000 Chr19:4863001- Actn3 2.867 4.023 3.308 4.433 3.907−1.040 4864000 Chr19:4930001- Peli3 1.867 4.193 3.723 2.433 3.807 −1.9404931000 Chr19:5038001- B3gnt1 0.867 3.608 2.723 4.240 3.000 −2.1335039000 Chr19:5116001- Klc2 2.452 4.023 2.723 4.017 3.700 −1.248 5117000Chr19:5388001- Sart1 0.867 4.023 2.723 1.433 2.807 −1.940 5389000Chr19:5425001- AI837181 1.867 4.023 4.045 3.433 3.459 −1.592 5426000Chr19:5480001- Efemp2 1.867 4.483 2.723 3.017 3.459 −1.592 5481000Chr19:57436001- Fam160b1 0.867 3.023 3.723 1.280 2.807 −1.940 57437000Chr19:5754001- Ltbp3 2.452 3.345 3.723 3.754 4.170 −1.718 5755000Chr19:59336001- Slc18a2 2.867 3.831 4.045 4.240 3.907 −1.040 59337000Chr19:6084001- Zfpl1 0.867 3.608 2.723 3.433 3.000 −2.133 6085000Chr19:6108001- Naaladl1 2.452 3.831 3.308 3.754 3.459 −1.007 6109000Chr19:6399001- Rasgrp2 0.715 1.023 3.308 3.017 3.000 −2.285 6400000Chr19:6981001- Prdx5 1.867 3.023 4.045 4.433 3.807 −1.940 6982000Chr19:7044001- Plcb3 1.867 2.023 3.308 2.433 3.000 −1.133 7045000Chr19:7277001- Otub1 2.452 1.023 3.308 4.754 4.000 −1.548 7278000Chr2:101519001- Traf6 2.452 4.345 3.308 3.754 3.000 −0.548 101520000Chr2:116727001- D330050G23Rik 2.452 4.023 4.045 3.754 4.000 −1.548116728000 Chr2:119097001- Rhov 2.452 3.023 2.723 4.017 3.459 −1.007119098000 Chr2:12846001- Pter 1.867 2.608 3.308 2.433 3.907 −2.04012847000 Chr2:130107001- Idh3b 1.867 2.608 1.723 4.017 3.585 −1.718130108000 Chr2:131030001- 2310035K24Rik 1.867 4.023 3.723 1.433 3.000−1.133 131031000 Chr2:132697001- Lrrn4 1.867 3.831 4.045 3.433 3.700−1.833 132698000 Chr2:143764001- Dstn 2.452 4.193 4.045 3.433 3.700−1.248 143765000 Chr2:143808001- Rrbp1 2.452 4.023 1.723 4.433 4.000−1.548 143809000 Chr2:146002001- 4930529M08Rik 3.452 4.023 4.045 4.7544.907 −1.455 146003000 Chr2:155074001- Dynlrb1 3.189 3.608 1.571 5.2404.248 −1.059 155075000 Chr2:155817001- Cep250 1.867 3.831 4.308 1.4333.807 −1.940 155818000 Chr2:160586001- Plcg1 2.192 4.608 2.723 4.2402.622 −0.430 160587000 Chr2:164667001- Pltp 2.452 4.193 4.045 3.0173.807 −1.355 164668000 Chr2:164719001- Pcif1 2.452 2.608 4.045 4.4333.585 −1.133 164720000 Chr2:173076001- Pmepa1 2.452 2.608 4.308 2.4333.459 −1.007 173077000 Chr2:174165001- Gnas 1.867 2.608 3.308 2.4333.000 −1.133 174166000 Chr2:174257001- Ctsz 0.867 4.023 3.723 3.7543.170 −2.303 174258000 Chr2:174287001- Atp5e 1.867 4.023 3.723 4.0173.807 −1.940 174288000 Chr2:176979001- Gm14410 2.452 2.023 3.723 3.7543.700 −1.248 176980000 Chr2:18923001- 4930426L09Rik 1.867 3.831 4.3084.433 3.322 −1.455 18924000 Chr2:25053001- A830007P12Rik 2.867 3.6084.308 3.433 4.087 −1.220 25054000 Chr2:25097001- 2310002J15Rik 0.8673.608 2.723 3.433 2.000 −1.133 25098000 Chr2:25129001- Anapc2 0.8674.345 2.723 3.017 4.000 −3.133 25130000 Chr2:25165001- Grin1 3.452 4.9304.893 4.017 4.459 −1.007 25166000 Chr2:25187001- AA543186 1.867 4.3453.308 4.017 3.170 −1.303 25188000 Chr2:25947001- Nacc2 1.867 4.023 3.3082.433 3.170 −1.303 25948000 Chr2:32181001- Dnm1 2.452 4.023 3.308 3.7543.459 −1.007 32182000 Chr2:35899001- Ndufa8 2.452 4.023 4.045 3.0173.459 −1.007 35900000 Chr2:91098001- Pacsin3 1.867 4.193 3.723 2.4333.807 −1.940 91099000 Chr2:92233001- Mapk8ip1 1.867 3.023 3.308 4.0173.459 −1.592 92234000 Chr2:94231001- Ttc17 1.867 4.023 1.723 3.433 4.644−2.777 94232000 Chr3:117529001- Snx7 2.867 3.345 3.308 4.240 4.248−1.381 117530000 Chr3:127339001- Neurog2 1.867 3.831 1.723 3.433 3.807−1.940 127340000 Chr3:151119001- Eltd1 3.452 3.608 4.531 4.433 4.524−1.072 151120000 Chr3:151905001- Nexn 2.867 3.608 4.308 4.017 3.907−1.040 151906000 Chr3:27894001- Pld1 1.867 2.023 3.308 2.433 3.000−1.133 27895000 Chr3:53251001- Nhlrc3 0.715 3.023 2.723 3.017 3.000−2.285 53252000 Chr3:63734001- E130311K13Rik 1.867 4.193 2.723 3.4333.170 −1.303 63735000 Chr3:68843001- Trim59 1.867 3.345 3.308 4.2403.322 −1.455 68844000 Chr4:101320001- Leprot 1.867 4.023 2.723 4.0173.000 −1.133 101321000 Chr4:107356001- Dmrtb1 1.867 3.345 3.308 2.4334.087 −2.220 107357000 Chr4:114588001- 9130206I24Rik 2.867 3.023 4.7234.240 3.907 −1.040 114589000 Chr4:116825001- Rps8 2.867 3.023 3.3084.602 4.000 −1.133 116826000 Chr4:118034001- Hyi 1.867 4.023 3.308 4.0173.000 −1.133 118035000 Chr4:122783001- Bmp8b 1.867 2.608 3.723 3.4333.000 −1.133 122784000 Chr4:123397001- Ndufs5 2.452 4.483 4.308 2.4333.807 −1.355 123398000 Chr4:123603001- Rragc 1.867 4.608 2.723 3.4333.459 −1.592 123604000 Chr4:125714001- Csf3r 1.867 3.608 3.723 3.4333.322 −1.455 125715000 Chr4:125925001- Mtap7d1 1.867 4.345 1.723 4.0173.585 −1.718 125926000 Chr4:126178001- Eif2c4 2.867 3.345 3.308 4.4334.644 −1.777 126179000 Chr4:128628001- Adc 2.452 4.608 2.723 4.017 3.700−1.248 128629000 Chr4:129054001- Zbtb8a 0.867 2.023 1.723 3.754 3.459−2.592 129055000 Chr4:130168001- Nkain1 2.452 3.345 4.531 3.017 3.585−1.133 130169000 Chr4:132961001- Slc9a1 1.867 4.193 2.723 3.017 3.700−1.833 132962000 Chr4:134478001- D4Wsu53e 0.867 3.608 3.308 3.754 4.000−3.133 134479000 Chr4:135029001- Nipal3 2.452 4.345 3.308 4.017 3.907−1.455 135030000 Chr4:135522001- Gale 0.867 3.023 3.723 3.754 3.322−2.455 135523000 Chr4:137115001- Hspg2 1.867 3.608 2.723 3.017 3.585−1.718 137116000 Chr4:138875001- Akr7a5 1.867 3.023 2.723 3.017 3.907−2.040 138876000 Chr4:140239001- Gm13025 1.867 2.608 1.723 3.754 3.807−1.940 140240000 Chr4:143112001- Gm13040 3.452 3.831 4.723 4.433 4.907−1.455 143113000 Chr4:143135001- Gm13057 3.452 4.483 4.531 4.433 4.907−1.455 143136000 Chr4:147322001- 2510039O18Rik 2.452 3.023 4.893 3.4333.807 −1.355 147323000 Chr4:147523001- Fbxo6 2.452 3.345 4.531 2.4333.585 −1.133 147524000 Chr4:147967001- Srm 2.452 4.345 4.045 3.754 3.459−1.007 147968000 Chr4:151462001- Plekhg5 1.867 3.023 3.308 2.433 3.170−1.303 151463000 Chr4:15202001- Tmem64 2.452 4.345 4.045 3.017 3.807−1.355 15203000 Chr4:155237001- Tas1r3 0.867 3.023 1.571 3.754 3.170−2.303 155238000 Chr4:35172001- 3110043O21Rik 1.867 3.023 2.723 3.4333.000 −1.133 35173000 Chr4:43055001- B230312A22Rik 2.452 3.831 3.7233.754 4.000 −1.548 43056000 Chr4:44994001- Grhpr 1.867 2.608 2.723 3.4333.807 −1.940 44995000 Chr4:45911001- E230008N13Rik 2.452 4.345 3.3083.754 3.700 −1.248 45912000 Chr4:48551001- 5730528L13Rik 2.452 3.8314.045 3.754 4.087 −1.635 48552000 Chr4:61926001- Slc31a2 1.867 2.6082.723 3.017 3.459 −1.592 61927000 Chr5:101081001- Coq2 2.452 3.345 3.3084.433 3.459 −1.007 101082000 Chr5:108154001- Gfi1 0.867 3.831 3.7233.754 2.585 −1.718 108155000 Chr5:110119001- 5430403G16Rik 0.715 3.8313.308 4.240 4.087 −3.372 110120000 Chr5:115891001- Msi1 2.452 2.6081.723 4.240 3.585 −1.133 115892000 Chr5:115963001- Pxn 2.452 3.831 4.0453.017 3.585 −1.133 115964000 Chr5:122303001- Fam109a 2.452 2.608 4.3083.017 3.585 −1.133 122304000 Chr5:122855001- Arpc3 0.867 4.483 3.3084.017 4.000 −3.133 122856000 Chr5:124312001- Niacr1 2.452 3.345 3.3083.754 3.459 −1.007 124313000 Chr5:135725001- Fzd9 1.867 4.608 3.3082.433 3.170 −1.303 135726000 Chr5:136213001- Tmem120a 1.867 0.871 4.3084.240 4.000 −2.133 136214000 Chr5:136625001- Orai2 1.867 3.345 2.7233.017 3.000 −1.133 136626000 Chr5:137548001- Serpine1 1.867 3.023 3.3082.433 3.700 −1.833 137549000 Chr5:138637001- Mblac1 1.867 3.023 4.3081.280 3.000 −1.133 138638000 Chr5:141093001- Lfng 1.867 3.345 1.7233.433 3.585 −1.718 141094000 Chr5:141183001- Baat1 2.452 3.831 4.5313.433 3.585 −1.133 141184000 Chr5:144952001- Bhlha15 1.867 3.345 3.7232.433 3.170 −1.303 144953000 Chr5:23948001- Fastk 2.452 4.345 4.0454.754 3.459 −1.007 23949000 Chr5:31202001- Agbl5 1.867 3.608 1.723 3.4333.000 −1.133 31203000 Chr5:34978001- Mfsd10 2.452 2.608 4.308 3.4333.585 −1.133 34979000 Chr5:42472001- Gm16223 1.867 2.608 2.723 3.0173.170 −1.303 42473000 Chr5:44227001- Bst1 2.452 4.023 4.531 4.017 4.087−1.635 44228000 Chr5:65875001- 1110003E01Rik 1.867 3.345 3.723 1.4333.459 −1.592 65876000 Chr5:67820001- Gm16714 2.867 3.831 4.531 3.4333.907 −1.040 67821000 Chr5:68240001- Gm15477 2.452 4.023 4.045 3.0173.807 −1.355 68241000 Chr5:96991001- Fras1 3.867 4.193 5.424 4.240 5.358−1.491 96992000 Chr5:97537001- Paqr3 0.867 3.345 4.045 4.240 2.807−1.940 97538000 Chr6:113236001- Cpne9 2.452 4.023 3.723 3.754 3.459−1.007 113237000 Chr6:113289001- Camk1 0.867 3.345 1.723 4.017 3.585−2.718 113290000 Chr6:113340001- Arpc4 2.867 3.023 2.723 4.602 4.000−1.133 113341000 Chr6:121216001- Usp18 2.452 3.345 2.723 4.017 3.700−1.248 121217000 Chr6:124344001- Pex5 2.452 3.608 3.308 3.754 3.807−1.355 124345000 Chr6:124715001- Eno2 2.452 4.023 3.308 3.754 3.585−1.133 124716000 Chr6:125095001- Iffo1 1.867 3.023 3.308 2.433 3.322−1.455 125096000 Chr6:126802001- Akap3 2.867 4.023 3.723 4.240 3.907−1.040 126803000 Chr6:129453001- Olr1 2.867 4.345 4.308 4.240 4.087−1.220 129454000 Chr6:29356001- Ccdc136 2.867 4.023 3.308 4.240 4.087−1.220 29357000 Chr6:36799001- Dgki 1.867 4.193 4.045 1.280 3.322 −1.45536800000 Chr6:47804001- Zfp398 3.189 4.193 4.308 4.240 4.700 −1.51147805000 Chr6:48359001- Krba1 2.867 3.831 4.308 3.433 3.907 −1.04048360000 Chr6:48546001- Repin1 1.867 4.345 2.723 3.433 3.700 −1.83348547000 Chr6:54640001- 2410066E13Rik 1.867 3.831 2.723 3.017 3.459−1.592 54641000 Chr6:83090001- Rtkn 1.867 3.608 1.571 4.017 3.170 −1.30383091000 Chr6:83104001- Wdr54 1.867 3.831 4.045 3.017 3.700 −1.83383105000 Chr6:85077001- Gm5878 2.452 3.608 4.045 3.433 3.459 −1.00785078000 Chr6:88860001- Tpra1 2.452 2.023 4.308 3.017 3.459 −1.00788861000 Chr6:89273001- Gm16896 2.452 3.608 1.571 4.433 3.700 −1.24889274000 Chr6:97766001- Mitf 2.867 3.023 4.308 3.433 4.392 −1.52597767000 Chr7:105333001- Gm16938 2.867 3.345 3.723 4.017 4.087 −1.220105334000 Chr7:105511001- Tsku 2.867 3.831 3.308 4.433 4.000 −1.133105512000 Chr7:107648001- Ucp2 0.867 3.831 3.723 4.240 3.322 −2.455107649000 Chr7:107660001- Dnajb13 2.867 4.023 4.045 4.240 3.907 −1.040107661000 Chr7:109361001- Pgap2 1.867 2.023 3.723 5.017 3.807 −1.940109362000 Chr7:111538001- Trim30c 3.189 4.193 4.531 4.240 4.248 −1.059111539000 Chr7:130607001- Aqp8 2.867 3.345 3.308 4.433 4.000 −1.133130608000 Chr7:13082001- Zfp606 1.867 4.023 4.045 3.017 3.459 −1.59213083000 Chr7:133942001- Aldoa 1.867 3.345 2.723 3.017 3.170 −1.303133943000 Chr7:134350001- Tbc1d10b 1.867 4.345 1.723 3.433 3.459 −1.592134351000 Chr7:134358001- SEPT_1 0.715 4.345 2.723 3.017 3.000 −2.285134359000 Chr7:134635001- Fbrs 0.867 3.023 3.308 3.017 3.907 −3.040134636000 Chr7:134978001- Stx4a 2.452 3.608 4.045 3.433 3.807 −1.355134979000 Chr7:135242001- Itgam 2.867 3.023 3.723 4.017 4.000 −1.133135243000 Chr7:148050001- Sirt3 0.867 3.608 3.723 3.754 3.700 −2.833148051000 Chr7:148396001- 1600016N20Rik 1.867 1.023 4.893 3.433 3.000−1.133 148397000 Chr7:148672001- Tspan4 0.867 4.345 4.308 3.754 3.585−2.718 148673000 Chr7:149244001- Mob2 1.867 3.608 1.723 3.433 3.170−1.303 149245000 Chr7:150970001- Mrgpre 1.867 3.831 1.723 4.017 4.000−2.133 150971000 Chr7:17478001- Gng8 0.867 3.345 3.308 3.017 3.459−2.592 17479000 Chr7:19713001- Fbxo46 2.867 3.831 3.308 4.240 3.907−1.040 19714000 Chr7:19799001- Gpr4 2.452 3.345 2.723 4.602 3.585 −1.13319800000 Chr7:20229001- Clptm1 2.452 3.023 4.045 3.017 3.585 −1.13320230000 Chr7:20320001- Pvrl2 2.452 4.193 4.045 3.433 3.459 −1.00720321000 Chr7:20352001- Bcam 2.452 4.193 4.045 4.602 3.700 −1.24820353000 Chr7:25169001- Kcnn4 1.867 2.023 3.308 4.017 3.322 −1.45525170000 Chr7:28453001- Map3k10 0.867 3.608 3.723 4.017 2.807 −1.94028454000 Chr7:29137001- Rps16 2.867 2.608 4.045 3.754 4.000 −1.13329138000 Chr7:29174001- Med29 1.867 3.345 4.531 3.017 3.700 −1.83329175000 Chr7:29329001- Nccrp1 2.452 3.023 3.308 3.754 3.585 −1.13329330000 Chr7:29513001- Fbxo17 2.867 3.831 3.723 4.602 4.000 −1.13329514000 Chr7:29669001- Capn12 2.867 3.023 4.723 3.433 4.170 −1.30329670000 Chr7:30555001- Zfp84 2.452 3.831 4.045 3.017 4.000 −1.54830556000 Chr7:30602001- Zfp790 2.867 3.345 4.531 3.433 4.322 −1.45530603000 Chr7:3112001- Gm7353 2.867 3.831 4.308 4.017 4.170 −1.3033113000 Chr7:31241001- Kirrel2 2.452 3.345 3.723 3.754 3.907 −1.45531242000 Chr7:3624001- Tmc4 2.452 3.345 3.308 4.017 3.807 −1.355 3625000Chr7:3758001- Pira5 3.452 4.483 5.183 3.433 4.907 −1.455 3759000Chr7:3866001- Lilra6 1.867 4.345 2.723 3.017 3.585 −1.718 3867000Chr7:4651001- Brsk1 2.867 3.608 4.045 3.754 4.248 −1.381 4652000Chr7:50743001- Iglon5 2.452 3.023 4.045 3.017 3.585 −1.133 50744000Chr7:51917001- Myh14 2.452 4.193 3.723 3.433 4.087 −1.635 51918000Chr7:52113001- Pnkp 1.867 3.608 3.723 3.433 3.585 −1.718 52114000Chr7:52122001- Ptov1 0.867 1.023 1.723 2.433 2.585 −1.718 52123000Chr7:52258001- Irf3 1.867 3.023 4.045 1.433 3.170 −1.303 52259000Chr7:52408001- Aldh16a1 2.452 3.023 3.308 3.754 3.907 −1.455 52409000Chr7:52901001- Mamstr 2.452 4.345 4.045 3.754 3.459 −1.007 52902000Chr7:53113001- Grin2d 2.452 3.023 3.308 3.754 3.807 −1.355 53114000Chr7:53971001- Saa3 2.452 4.193 3.308 4.433 3.907 −1.455 53972000Chr7:69619001- Atp5l-ps1 3.452 2.608 4.893 4.433 4.807 −1.355 69620000Chr7:86857001- Kif7 2.452 3.345 4.308 3.017 3.585 −1.133 86858000Chr7:86958001- Mesp2 2.452 3.831 4.045 4.017 3.807 −1.355 86959000Chr7:87188001- Zfp710 1.867 3.345 2.723 3.017 3.700 −1.833 87189000Chr7:87333001- Sema4b 2.867 4.023 3.723 4.017 3.907 −1.040 87334000Chr7:87472001- Unc45a 1.867 3.345 3.308 2.433 3.322 −1.455 87473000Chr7:95676001- Gm10159 2.452 3.608 3.308 3.754 4.170 −1.718 95677000Chr8:107870001- Fhod1 0.867 3.023 3.723 3.754 3.700 −2.833 107871000Chr8:107879001- Slc9a5 1.867 4.724 1.723 3.433 3.459 −1.592 107880000Chr8:108050001- Atp6v0d1 1.867 3.608 3.308 2.433 3.170 −1.303 108051000Chr8:108380001- Thap11 2.452 3.345 4.308 3.754 3.585 −1.133 108381000Chr8:108469001- Gm16156 2.452 3.831 3.723 4.240 3.700 −1.248 108470000Chr8:114259001- Bcar1 1.867 3.023 2.723 3.017 4.322 −2.455 114260000Chr8:114397001- Tmem170 0.867 3.608 3.723 3.017 3.700 −2.833 114398000Chr8:15026001- Kbtbd11 2.452 2.023 2.723 4.017 3.585 −1.133 15027000Chr8:26202001- Plekha2 1.867 3.345 1.723 3.433 3.322 −1.455 26203000Chr8:28086001- Zfp703 2.867 3.023 3.723 4.017 4.170 −1.303 28087000Chr8:28137001- Erlin2 2.452 2.608 2.723 4.240 3.807 −1.355 28138000Chr8:37088001- Gm10063 0.867 4.608 1.723 2.433 3.170 −2.303 37089000Chr8:4135001- Cd209g 2.452 3.608 3.308 3.754 3.459 −1.007 4136000Chr8:4245001- Map2k7 0.867 3.608 3.308 1.280 2.585 −1.718 4246000Chr8:4681001- Gm6410 3.189 4.023 4.531 4.017 4.248 −1.059 4682000Chr8:48763001- AA386476 2.452 3.608 2.723 4.433 3.459 −1.007 48764000Chr8:72447001- Gatad2a 1.867 4.193 2.723 3.017 3.700 −1.833 72448000Chr8:72822001- Ddx49 1.867 4.345 3.308 2.433 3.585 −1.718 72823000Chr8:73039001- 2810422J05Rik 2.867 3.608 3.723 4.240 4.000 −1.13373040000 Chr8:73140001- Lrrc25 1.867 4.724 2.723 3.433 3.000 −1.13373141000 Chr8:73198001- Lsm4 2.452 0.871 3.723 4.602 3.907 −1.45573199000 Chr8:73257001- Pde4c 1.867 3.608 2.723 3.017 3.000 −1.13373258000 Chr8:73408001- Slc5a5 1.867 4.193 3.723 1.433 3.907 −2.04073409000 Chr8:73789001- Haus8 1.867 3.345 2.723 3.017 4.000 −2.13373790000 Chr8:74087001- Nxnl1 2.867 3.023 3.723 4.017 3.907 −1.04074088000 Chr8:74114001- Pgls 2.452 4.023 4.045 3.017 3.807 −1.35574115000 Chr8:85688001- Gm10645 2.452 3.023 3.308 3.754 3.907 −1.45585689000 Chr8:86649001- Podnl1 1.867 3.023 2.723 3.017 3.170 −1.30386650000 Chr8:87542001- Asna1 2.452 4.193 3.308 3.754 3.700 −1.24887543000 Chr8:98339001- 4930513N10Rik 1.867 4.023 2.723 4.240 3.700−1.833 98340000 Chr9:106346001- Abhd14a 2.452 2.608 4.308 2.433 3.459−1.007 106347000 Chr9:107444001- Cyb561d2 1.867 2.608 2.723 3.433 3.700−1.833 107445000 Chr9:107476001- Hyal2 1.867 4.345 1.723 3.754 3.700−1.833 107477000 Chr9:114277001- 4930520O04Rik 0.867 3.023 2.723 3.4333.000 −2.133 114278000 Chr9:114399001- Ccr4 2.452 3.608 4.045 3.4334.000 −1.548 114400000 Chr9:119392001- Scn5a 2.867 3.831 3.723 4.0174.000 −1.133 119393000 Chr9:120484001- Rpl14 2.867 4.023 4.531 3.7544.322 −1.455 120485000 Chr9:122933001- Tmem42 2.452 4.345 3.723 3.4333.700 −1.248 122934000 Chr9:15393001- Ccdc67 2.452 4.193 2.723 4.0173.700 −1.248 15394000 Chr9:20453001- Ubl5 2.452 3.608 1.723 5.017 4.392−1.940 20454000 Chr9:20876001- Fdx1l 0.867 2.023 3.723 3.754 3.459−2.592 20877000 Chr9:21150001- Slc44a2 2.867 4.608 4.045 4.017 3.907−1.040 21151000 Chr9:21932001- Acp5 2.867 2.608 4.308 3.433 3.459 −0.59221933000 Chr9:22087001- Zfp810 2.867 3.608 2.723 4.754 4.170 −1.30322088000 Chr9:24933001- Herpud2 2.452 3.023 2.723 4.017 4.322 −1.87024934000 Chr9:35236001- Cdon 2.867 4.345 4.045 3.754 3.907 −1.04035237000 Chr9:42062001- Sc5d 2.867 3.831 4.308 4.017 3.907 −1.04042063000 Chr9:44577001- Ift46 2.452 3.023 4.045 3.017 4.087 −1.63544578000 Chr9:46078001- Apoa5 1.867 4.023 2.723 3.433 3.000 −1.13346079000 Chr9:50573001- 1110032A03Rik 0.867 4.193 1.723 4.602 3.322−2.455 50574000 Chr9:55205001- AI118078 2.452 4.193 4.308 2.433 3.907−1.455 55206000 Chr9:57001001- Commd4 2.867 3.023 4.045 4.433 4.000−1.133 57002000 Chr9:57109001- 1700017B05Rik 1.867 1.023 1.571 3.7543.000 −1.133 57110000 Chr9:59453001- Celf6 1.867 4.483 2.723 4.017 3.807−1.940 59454000 Chr9:59506001- Pkm2 2.452 3.831 1.723 4.240 3.585 −1.13359507000 Chr9:62715001- Gm10653 1.867 4.345 1.723 3.433 4.585 −2.71862716000 Chr9:65061001- Parp16 2.452 4.023 4.045 3.433 3.700 −1.24865062000 Chr9:66648001- BC050972 1.867 4.193 2.723 3.433 3.700 −1.83366649000 Chr9:70507001- Gm10642 2.867 4.193 1.723 4.602 4.524 −1.65770508000 Chr9:78092001- Dppa5b 1.867 3.831 3.723 3.754 3.000 −1.13378093000 Chr9:7838001- C330006D17Rik 1.867 3.345 3.723 3.017 3.585−1.718 7839000 Chr9:81538001- D430036J16Rik 2.452 5.111 3.723 4.4334.087 −1.635 81539000 Chr9:86462001- Pgm3 1.867 4.483 3.308 2.433 3.459−1.592 86463000 ChrX:12195001- Atp6ap2 1.867 1.023 4.045 1.433 3.000−1.133 12196000 ChrX:15513001- Drr1 2.452 3.608 4.045 4.240 4.700 −2.24815514000 ChrX:34911001- Rhox2d 0.867 1.023 3.308 3.017 3.459 −2.59234912000 Cleavage in any region and don't show differential expressionChr1:146619001- Rgs18 4.189 2.608 1.723 1.433 2.585 1.604 146620000Chr1:159290001- Rasal2 2.867 1.023 1.571 2.433 3.000 −0.133 159291000Chr1:166005001- Sell 5.115 3.023 3.308 1.433 4.524 0.591 166006000Chr1:196548001- Plxna2 4.954 3.345 2.723 1.433 3.459 1.495 196549000Chr1:37087001- Vwa3b 5.259 2.023 3.308 2.433 3.807 1.452 37088000Chr1:44709001- Gulp1 5.037 1.023 3.308 3.433 3.807 1.230 44710000Chr1:60466001- Abi2 4.037 3.023 1.571 1.280 2.000 2.037 60467000Chr1:65410001- Pth2r 4.189 2.023 1.571 3.017 3.585 0.604 65411000Chr1:70884001- Vwc2l 4.452 0.871 3.723 2.433 3.000 1.452 70885000Chr10:13276001- Adat2 4.189 1.023 1.571 3.017 3.459 0.730 13277000Chr11:58088001- 4930438A08Rik 4.674 1.023 3.723 2.433 3.000 1.67458089000 Chr11:67609001- Dhrs7c 4.954 3.023 1.723 3.433 3.459 1.49567610000 Chr11:97066001- Npepps 0.867 0.871 1.571 1.280 1.585 −0.71897067000 Chr12:114952001- Gm16594 4.452 1.023 1.571 1.433 3.322 1.130114953000 Chr12:67657001- Mdga2 4.189 0.871 3.308 2.433 3.807 0.38267658000 Chr12:76023001- Kcnh5 4.452 2.608 1.723 1.280 3.170 1.28276024000 Chr12:85792001- Lin52 4.326 2.023 1.571 2.433 3.807 0.51985793000 Chr12:88997001- BB287469 0.715 0.871 1.571 1.280 −0.152 0.86788998000 Chr13:105254001- Adamts6 3.089 2.023 1.571 1.280 3.585 −0.496105255000 Chr13:27941001- Prl2c1 4.674 3.023 2.723 1.280 3.000 1.67427942000 Chr13:39952001- U1 4.452 2.023 2.723 2.433 3.322 1.130 39953000Chr13:62252001- Zfp808 4.037 1.023 1.723 1.433 3.807 0.230 62253000Chr13:63532001- Fancc 3.189 2.023 1.723 1.280 1.585 1.604 63533000Chr13:63963001- 0610007P08Rik 3.867 2.023 1.723 1.433 1.585 2.28263964000 Chr13:67199001- Zfp708 4.774 2.023 3.723 1.280 3.585 1.18967200000 Chr14:17610001- Rarb 3.067 2.608 1.723 1.280 3.700 −0.63317611000 Chr14:19507001- Ube2e2 3.867 1.023 1.571 3.017 2.322 1.54519508000 Chr14:63628001- Defb43 4.567 2.608 3.308 1.280 3.000 1.56763629000 Chr14:79733001- Naa16 4.037 2.608 1.723 1.280 3.807 0.23079734000 Chr15:54105001- Tnfrsf11b 4.674 2.608 3.723 1.280 2.585 2.08954106000 Chr15:7207001- Egflam 4.954 2.023 3.723 3.017 3.700 1.2547208000 Chr15:91341001- Slc2a13 4.567 2.023 1.723 2.433 3.322 1.24691342000 Chr16:50529001- G730013B05Rik 4.189 2.023 2.723 1.433 2.5851.604 50530000 Chr16:96367001- Wrb 4.037 2.023 1.723 2.433 4.087 −0.05196368000 Chr17:35480001- H2-Q2 2.452 1.023 1.571 1.433 1.585 0.86735481000 Chr17:52907001- Kcnh8 3.867 2.023 2.723 1.433 2.585 1.28252908000 Chr19:29999001- Il33 4.326 2.608 1.723 1.433 3.807 0.51930000000 Chr19:30250001- Gldc 4.567 2.023 3.723 1.280 3.000 1.56730251000 Chr2:103271001- Elf5 4.189 2.023 1.571 2.433 3.700 0.489103272000 Chr2:147699001- U6 4.037 1.023 1.571 2.433 2.322 1.715147700000 Chr2:17445001- Nebl 4.326 3.023 1.571 1.433 3.459 0.86717446000 Chr2:178164001- Cdh26 3.674 2.023 1.723 1.433 2.000 1.674178165000 Chr2:3631001- Fam107b 4.189 2.023 1.571 3.017 2.322 1.8673632000 Chr2:36667001- Olfr3 4.567 2.608 2.723 1.433 0.000 4.56736668000 Chr2:5182001- U2 4.037 2.608 1.571 1.280 2.585 1.452 5183000Chr2:52189001- Neb 4.867 1.023 2.723 3.017 3.700 1.167 52190000Chr2:6159001- A230108P19Rik 4.326 1.023 1.723 3.017 3.807 0.519 6160000Chr2:82806001- Fsip2 4.452 1.023 1.723 3.017 3.459 0.993 82807000Chr3:101408001- Atp1a1 4.452 3.023 1.571 2.433 3.322 1.130 101409000Chr3:105490001- Ddx20 3.452 1.023 1.723 1.280 4.392 −0.940 105491000Chr3:122843001- Synpo2 4.774 3.023 1.571 2.433 3.907 0.867 122844000Chr3:19231001- 7SK 3.189 1.023 1.571 2.433 2.585 0.604 19232000Chr3:33290001- SNORA48 4.452 2.023 2.723 2.433 2.322 2.130 33291000Chr3:39700001- SNORA17 3.452 0.871 1.723 1.433 3.000 0.452 39701000Chr3:80921001- Pdgfc 3.674 1.023 1.571 2.433 2.322 1.352 80922000Chr3:83959001- Mnd1 1.867 1.023 1.571 1.433 2.585 −0.718 83960000Chr3:85157001- Arfip1 4.567 0.871 3.308 3.433 4.170 0.398 85158000Chr4:109321001- Gm12811 4.326 2.023 2.723 2.433 3.807 0.519 109322000Chr4:134319001- Ldlrap1 4.954 2.023 2.723 2.433 3.585 1.370 134320000Chr4:19331001- Cngb3 4.452 3.345 1.723 1.433 2.807 1.645 19332000Chr4:3943001- Sdr16c5 4.452 2.023 2.723 2.433 3.459 0.993 3944000Chr4:59130001- AI481877 4.867 3.023 3.308 1.280 3.700 1.167 59131000Chr4:61060001- Mup15 3.867 2.023 1.723 1.280 3.322 0.545 61061000Chr4:95349001- Fggy 5.259 3.023 3.308 3.017 3.700 1.559 95350000Chr5:127787001- Tmem132c 3.867 2.023 1.571 1.433 3.170 0.697 127788000Chr5:143871001- Rnf216 3.867 1.023 1.571 3.017 3.000 0.867 143872000Chr5:3397001- Cdk6 4.867 3.023 2.723 2.433 3.000 1.867 3398000Chr5:96390001- Cxcl13 4.567 1.023 3.308 3.017 3.000 1.567 96391000Chr5:9704001- Grm3 3.452 2.023 1.723 1.280 3.170 0.282 9705000Chr6:67321001- Il12rb2 4.452 2.023 2.723 2.433 3.322 1.130 67322000Chr6:87777001- Isy1 4.452 1.023 3.308 1.280 3.000 1.452 87778000Chr7:109121001- Numa1 3.674 1.023 1.723 1.433 3.170 0.504 109122000Chr7:10945001- Nlrp4d 4.326 2.608 2.723 1.280 3.000 1.326 10946000Chr7:114032001- Olfr706 4.954 2.023 3.308 3.017 1.585 3.370 114033000Chr7:135137001- Pycard 4.674 2.023 2.723 2.433 3.000 1.674 135138000Chr7:22454001- Gm4545 0.867 0.871 1.723 1.280 −0.152 1.019 22455000Chr7:66704001- SNORD115 2.867 1.023 1.571 1.280 3.170 −0.303 66705000Chr7:68880001- Mir344e 3.867 2.023 1.571 2.433 2.585 1.282 68881000Chr7:79223001- Mctp2 4.189 1.023 2.723 2.433 2.322 1.867 79224000Chr7:92563001- Vmn2r69 4.674 3.023 1.723 2.433 3.170 1.504 92564000Chr8:46798001- Sorbs2 4.452 0.871 3.723 2.433 3.170 1.282 46799000Chr8:48627001- Rwdd4a 4.326 2.023 1.723 2.433 4.392 −0.066 48628000Chr8:55162001- Vegfc 3.867 0.871 3.308 1.433 2.000 1.867 55163000Chr9:103220001- Topbp1 5.115 2.608 3.308 3.433 2.585 2.530 103221000Chr9:108982001- Ccdc72 3.867 1.023 2.723 1.433 4.322 −0.455 108983000Chr9:39200001- Olfr951 5.037 3.831 1.571 2.433 4.170 0.867 39201000Chr9:54323001- Dmxl2 4.954 3.023 1.723 3.017 3.907 1.048 54324000Chr9:73361001- Unc13c 4.567 2.608 1.571 3.433 2.585 1.982 73362000Chr9:7763001- Tmem123 4.189 1.023 2.723 1.433 3.322 0.867 7764000ChrX:144496001- U3 2.867 0.871 1.723 1.433 1.585 1.282 144497000ChrX:51094001- Xlr 4.037 3.023 1.723 1.280 2.585 1.452 51095000ChrX:74032001- 5S_rRNA 2.867 1.023 1.571 1.433 2.585 0.282 74033000ChrX:91596001- snoU13 3.674 1.023 1.571 2.433 2.000 1.674 91597000ChrX:98440001- U11 4.189 2.023 2.723 1.280 3.700 0.489 98441000

What is claimed is:
 1. A method to identify a polynucleotide fragmentbound to an H3 histone comprising a cleaved N-terminal tail (H3NT) in acell, the method comprising: a. crosslinking the genomic DNA of the cellto the histones of the cell, thereby producing crosslinked chromatin; b.generating fragments of the crosslinked chromatin; c. acetylating allunmodified lysine residues in the histones by contacting the fragmented,crosslinked chromatin with acetic anhydride or an equivalent thereof; d.conducting parallel chromatin immunoprecipitations on the acetylatedchromatin produced in step c. with (1) an H3 C-terminal tail controlantibody and (2) one or more antibodies directed to acetylated lysineresidues in the cleaved region of the H3NT; and e. identifying thepolynucleotide fragment bound to an H3NT by detecting reduction inpolynucleotide fragment enrichment with the one or more antibodiesdirected to acetylated lysine residues in the cleaved region relative topolynucleotide fragment enrichment with the H3 C-terminal tail controlantibody.
 2. The method of claim 1, wherein step a. is performed byfixation with methylene blue or an equivalent thereof.
 3. The method ofclaim 1, wherein step b. is performed by sonication, enzymaticfragmentation, or an equivalent of each thereof.
 4. The method of claim1, wherein the one or more antibodies directed to acetylated lysineresidues in the cleaved region of the H3NT are selected from an H3K4acantibody, an H3K9ac antibody, and an H3K14ac antibody.
 5. The method ofclaim 4, wherein the one or more antibodies directed to acetylatedlysine residues in the cleaved region of the H3NT is an H3K14acantibody.
 6. The method of claim 1, wherein step e. is performed by amethod comprising quantitative PCR (qPCR) or NextGen sequencinganalysis.
 7. The method of claim 1, further comprising identifying asubject for therapy with MMP-9.
 8. The method of claim 1, furthercomprising identifying a region of the genome of the cell at which amatrix metalloproteinase cleaves an H3 N terminal tail.
 9. A method tomodulate H3NT proteolysis in a cell, comprising modulating the activityof MMP-9 in the cell.
 10. The method of claim 9, wherein the H3NTproteolysis is increased by increasing MMP-9 activity in the nucleus ofthe cell.
 11. The method of claim 10, wherein the MMP-9 activity isincreased by one or more of: increasing nuclear localization of MMP-9,increasing acetylation of H3K18 residues, and/or overexpression ofMMP-9.
 12. The method of claim 9, wherein the H3NT proteolysis isdecreased by depletion or inhibition of MMP-9 activity in the cell. 13.The method of claim 12, wherein the MMP-9 activity is decreased by oneor more of: knockdown of MMP-9 mRNA, treatment with CBP/p300 inhibitor,or treatment with a metalloprotease inhibitor.
 14. The method of claim13, wherein knockdown of MMP-9 mRNA comprises administration of aneffective amount of MMP-9 shRNA to the cell and/or contacting the cellwith an effective amount of a mesenchymal stem cell expressing MMP-9shRNA.
 15. The method of claim 9, wherein the activity of MMP-9 is invitro or in vivo.
 16. The method of claim 1 or 9, wherein the cell is amammalian cell.
 17. The method of 16 wherein the mammalian cell is anosteoclast or osteoclast precursor cell.
 18. A method to attenuateosteoclast formation and/or differentiation in a subject, comprisingadministering to the subject an effective amount of a MMP-9 agent orinhibitor to the subject.
 19. A method of treating a subject with lowbone mineral density, comprising administering an effective amount of anagent that decreases or inhibits the activity of MMP-9 in the subject.20. The method of claim 18 or 19, wherein the agent is selected fromMMP-9 shRNA, a mesenchymal stem cell expressing MMP-9 shRNA, a CBP/p300inhibitor, an MMP-9 inhibitor, or a metalloprotease inhibitor.
 21. Amethod of treating a subject with high bone mineral density, comprisingadministering to the subject an effective amount of an agent thatincreases the activity of MMP-9 in the subject.
 22. The method of claim21, wherein the agent is one ore more of: MMP-9, MMP-9 modified toinclude nuclear localization signals, a histone acetyltransferase enzymewith H3K18 specificity, and a polynucleotide encoding MMP-9.
 23. Themethod of claim 19, wherein the subject has a bone related disease orcondition selected from osteoporosis, bone cancer, cancer that hasmetastasized to the bone, cancer-induced osteolysis, sepsis, rheumatoidarthritis, and periodontitis.
 24. The method of claim 21, wherein thesubject has a bone related disease or condition selected fromosteopetrosis, pycondysostosis, osteopoikilosis, meloreostosis,sclerosteosis, van Buchem's disease, LRP5 high bone mass, LRP4 high bonemass, craniometaphyseal dysplasia, Camurati-Engelmann disease, Ghosalsyndrome, bone cancer, cancer metastasized to the bone, fluorosis, renalosteodystrophy, acromegaly, hepatitis C-associated osteosclerosis,myelofibrosis, mastocytosis, osseous tuberous sclerosis, Paget'sdisease, and SAPHO syndrome.
 25. A kit for identifying a polynucleotidefragment bound to an H3 histone comprising a cleaved N-terminal tail(H3NT) in a cell, the kit comprising: a. acetic anhydride or anequivalent thereof; b. an H3 C-terminal tail control antibody; c. anH3K14ac antibody; and d. instructions for use.